Antibiotic oxazolidinone derivatives

ABSTRACT

The present invention relates to antibiotic compounds and in particular to antibiotic compounds containing an oxazolidinone ring. This invention further relates to processes for their preparation, to intermediates useful in their preparation, to their use as therapeutic agents and to pharmaceutical compositions containing them.

This application is a divisional of U.S. Ser. No. 08/945,160, now U.S.Pat. No. 5,981,528 which is a national stage filing under 35 U.S.C. §371(e) of International Application No. PCT/GB97/00462, filed on Feb. 20,1997.

The present invention relates to antibiotic compounds and in particularto antibiotic compounds containing an oxazolidinone ring. This inventionfurther relates to processes for their preparation, to intermediatesuseful in their preparation, to their use as therapeutic agents and topharmaceutical compositions containing them.

The international microbiological community continues to express seriousconcern that the evolution of antibiotic resistance could result instrains against which currently available antibacterial agents will beineffective. In general, bacterial pathogens may be classified as eitherGram-positive or Gram-negative pathogens. Antibiotic compounds witheffective activity against both Gram-positive and Gram-negativepathogens are generally regarded as having a broad spectrum of activity.The compounds of the present invention are regarded primarily aseffective against Gram-positive pathogens because of their particularlygood activity against such pathogens.

Gram-positive pathogens, for example Staphylococci, Enterococci,Streptococci and mycobacteria, are particularly important because of thedevelopment of resistant strains which are both difficult to treat anddifficult to eradicate from the hospital environment once established.Examples of such strains are methicillin resistant staphylococcus(MRSA), methicillin resistant coagulase negative staphylococci (MRCNS),penicillin resistant streptococcus pneumoniae and multiply resistantEnterococcus faecium.

The major clinically effective antibiotic for treatment of suchresistant Gram-positive pathogens is vancomycin. Vancomycin is aglycopeptide and is associated with nephrotoxicity and ototoxicity.Furthermore, and most importantly, antibacterial resistance tovancomycin and other glycopeptides is also appearing. This resistance isincreasing at a steady rate rending theses agents less and lesseffective in the treatment of Gram-positive pathogens.

The present inventors have discovered a class of antibiotic compoundscontaining an oxazolidinone ring which has useful activity againstGram-positive pathogens including MRSA and MRCNS and, in particular,against various strains exhibiting resistance to vancomycin and againstE. faecium strains resistant to both aminoglycosides and clinically usedβ-lactams.

We have now discovered a narrow range of compounds that is not suggestedby the art and which has good activity against a broad range ofGram-positive pathogens including organisms known to be resistant tomost commonly used antibiotics. In comparison with compounds describedin the art (for example Walter A. Gregory et al in J. Med. Chem. 1990,33, 2569-2578 and Chung-Ho Park et al in J. Med. Chem. 1992, 35,1156-1165) the compounds also posses a favourable toxicological profile.

Accordingly the present invention provides a compound of the formula(I):

wherein:

R¹ is hydroxy, chloro, fluoro, (1-4C)alkanesulfonyloxy, amino, azido,(1-4C)alkoxy, (1-4C)alkythio, (1-4C)alkylaminocarbonyloxy;

or the formula —NHC(═O)R^(b) wherein R^(b) is hydrogen, (1-4C)alkoxy,amino, chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl,acetylmethyl, methylamino, dimethylamino or (1-4C)alkyl;

or R¹ is of the formula —NHS(O)_(n)(1-4C)alkyl wherein n is 0, 1 or 2;

R² and R³ are independently hydrogen or fluoro;

D is O, S, SO, SO₂ or NR⁷;

when D is O, R⁴ and R⁵ are independently hydroxy, bromo, oxo (═O),(1-4C)alkyl, (1-4C)alkanoylamino-(1-4C)alkyl, hydroxy-(1-4C)alkyl,carboxy, (1-4C)alkoxycarbonyl, AR-oxymethyl, AR-thiomethyl (wherein ARis as defined hereinbelow) or independently as defined for R⁷hereinbelow;

when D is S, SO, SO₂ or NR⁷, R⁴ and R⁵ are independently oxo (═O),(1-4C)alkyl, (1-4C)alkanoylamino-(1-4C)alkyl, hydroxy-(1-4C)alkyl,carboxy, (1-4C)alkoxycarbonyl, AR-oxymethyl, AR-thiomethyl (wherein ARis as defined hereinbelow) or independently as defined for R⁷hereinbelow;

R⁶ is hydrogen, (1-4C)alkyl, hydroxy, (1-4C)alkoxy or (2-4C)alkanoyloxy;

>A—B— is of the formula >C═(R^(a))—, >CHCHR^(a)—, or>C(OH)CHR^(a)—(>represents two single bonds) wherein R^(a) is hydrogenor (1-4C)alkyl;

R⁷ is hydrogen, cyano, 2-((1-4C)alkoxycarbonyl)ethenyl, 2-cyanoethenyl,2-cyano-2-((1-4C)alkyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl, AR(as defined hereinbelow) or a tetrazole ring system (optionallymono-substituted in the 1- or 2-position of the tetrazole ring) whereinthe tetrazole ring system is joined to the nitrogen in NR⁷ by a ringcarbon atom;

or R⁷ is of the formula R¹⁰CO—, R¹⁰SO₂—, R¹⁰CS—

wherein R¹⁰ is AR (as defined hereinbelow), cyclopentyl or cyclohexyl(wherein the last two-mentioned cycloalkyl rings are optionally mono- ordisubstituted by substituents independently selected from (1-4C)alkyl(including geminal disubstitution), hydroxy, (1-4C)alkoxy,(1-4C)alkylthio, acetamido, (1-4C)alkanoyl, cyano and trifluoromethyl),(1-4C)alkoxycarbonyl, hydrogen, amino, trifluoromethyl,(1-4C)alkylamino, di((1-4C)alkyl)amino,2,3-dihydro-5-oxothiazolo-[3,2-A]pyrimidin-6-yl, 2-(2-furyl)ethenyl,2-(2-thienyl)ethenyl,2-phenylethenyl (wherein the phenyl substituent isoptionally substituted by up to three substituents independentlyselected from (1-4C)alkoxy, halo and cyano), 3,4-dihydropyran-2-yl,coumal-5-yl, 5-methoxy-4-oxopyran-2-yl, N-acetylpyrrolidin-2-yl,5-oxo-tetrahydrofuran-2-yl, benzopyranone or (1-10C)alkyl [wherein(1-10C)alkyl is optionally substituted by hydroxy, cyano, halo(1-10C)alkoxy, trifluoromethyl, (1-4C)alkoxy-(1-4C)alkoxy,(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkanoyl,(1-4C)alkoxycarbonyl, amino, (1-4C)alkylamino, di((1-4C)alkyl)amino,(1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino,N-(1-4C)alkyl-N-(2-6C)alkanoylamino, (1-4C)alkylS(O)_(p)NH—,(1-4C)alkylS(O)_(p)((1-4C)alkyl)N—, fluoro(1-4C)alkylS(O)₉NH—,fluoro(1-4C)alkylS(O)_(p)((1-4C)alkyl)N—, phosphono,1-4C)alkoxy(hydroxy)phosphoryl, di-(1-4C)alkoxyphosphoryl,(1-4C)alkylS(O)_(q)—, phenylS(O)_(q)— (wherein the phenyl group isoptionally substituted by up to three substituents independentlyselected from (1-4C)alkoxy, halo and cyano), or CY (as definedhereinbelow), wherein p is 1 or 2 and q is 0.1 or 2];

or R¹⁰ is of the formula R¹¹C(O)O(1-6C)alkyl wherein R¹¹ is anoptionally substituted 5- or 6-membered heteroaryl, optionallysubstituted phenyl, (1-4C)alkylamino, benzyloxy-(1-4C)alkyl oroptionally substituted (1-10C)alkyl;

or R¹⁰ is of the formula R¹²O— wherein R¹² is optionally substituted(1-6C)alkyl;

or R⁷ is of the formula R^(d)OC(R^(e))═CH(C═O), R^(f)C(═O)—,R^(g)N═C(R^(h))C(═O)— or R^(i)NHC(R^(j))═CHC(═O)— wherein R^(d) is(1-6C)alkyl, R^(e) is hydrogen or (1-6C)alkyl, or R^(d) and R^(e)together form a (3-4C)alkylene chain, R^(f) is hydrogen, (1-6C)alkyl,hydroxy(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, amino, (1-4C)alkylamino,di-(1-4C)alkylamino, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy,hydroxy(2-6C)alkoxy, (1-4C)alkylamino(2-6C)alkoxy,di-(1-4C)alkylamino(2-6)alkoxy, R^(g) is (1-6C)alkyl, hydroxy or(1-6C)alkoxy, R^(h) is hydrogen or (1-6C)alkyl, R^(i) is hydrogen(1-6C)alkyl, optionally substituted phenyl or an optionally substituted5- or 6-membered heteroaryl and R^(j) is hydrogen or (1-6C)alkyl;

or R⁷ is of the formula R¹⁴(CH(R¹³)(CH₂)_(m)— wherein m is 0 or 1, R¹³is fluoro, cyano, (1-4C)alkoxy, (1-4C)alkylsulfonyl,(1-4C)alkoxycarbonyl or hydroxy, (provided that when m is 0, R¹³ is notfluoro or hydroxy) and R¹⁴ is hydrogen or (1-4C)alkyl

wherein AR is optionally substituted phenyl, optionally substitutedphenyl(1-4C)alkyl, optionally substituted 5- or 6-membered heteroaryl,optionally substituted naphthyl or an optionally substituted 5/6 or 6/6bicyclic heteroaryl ring system, in which the bicyclic heteroaryl ringsystems may be linked via an atom in either of the rings comprising thebicyclic system, and wherein the mono- and bicyclic heteroaryl ringsystems are linked via a ring carbon atom;

wherein CY is a 4-, 5- or 6-membered cycloalkyl ring, a 5- or 6-memberedcycloalkenyl ring, naphthoxy, thiophen-2-yl, indol-1-yl, indol-3-yl,pyrimidin-2-ylthio, 1,4-benzodioxan-6-yl, sulfolan-3-yl, pyridin-2-yl;wherein any of the afore-mentioned ring systems in CY may be optionallysubstituted by up to three substituents independently selected formhalo, (1-4C)alkyl (including geminal disubstitution when CY is acycloalkyl or cycloalkenyl ring), acyl, oxo and nitro-(1-4C)alkyl; andpharmaceutically-acceptable salts thereof; except that

N-((5S)-3-(4-(2-oxo-5,6-dihydropyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamideis excluded.

In this specification a ‘5- or 6-membered heteroaryl’ and ‘heteroaryl(monocyclic) ring’ means a 5- or 6-membered aryl ring wherein 1, 2 or 3of the ring atoms are selected from nitrogen, oxygen and sulfur.Particular examples of 5- or 6-membered heteroaryl ring systems arefuran, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine,pyridine, isoxazole, oxazole, isothiazole, thiazole and thiophene.

In this specification a ‘5/6 or 6/6 bicyclic heteroaryl ring system’ and‘heteroaryl (bicyclic) ring’ means an aromatic bicyclic ring systemcomprising a 6-membered ring fused to either a 5 membered ring oranother 6 membered ring, the bicyclic ring system containing 1 to 4heteroatoms selected from nitrogen, oxygen and sulfur. Particularexamples of 5/6 and 6/6 bicyclic ring systems are indole, benzofuran,benzoimidazole, benzothiophene, benzisothiazole, benzoxazole,benzisoxazole, pyridoimidazole, pyrimidoimidazole, quinoline,quinoxaline, quinazoline, phthalozine, cinnoline and naphthyridine.

In this specification of ‘4-, 5- or 6-membered cycloalkyl ring’ means acyclobutyl, cyclopentyl or cyclohexyl ring; and a ‘5- or 6-memberedcycloalkenyl ring ’ means cyclopentenyl or cyclohexenyl ring.

In this specification the term ‘alkyl’ includes straight chained andbranched structures. For example, (1-6C)alkyl includes propyl, isopropyland tert-butyl. However, references to individual alkyl groups such as“propyl” are specific for the straight chained version only, andreferences to individual branched chain alkyl groups such as “isopropyl”are specific for the branched chain version only. A similar conventionapplies to other radicals, for example halo(1-4C)alkyl includes1-bromoethyl and 2-bromoethyl.

Particular optional substituents for alkyl, phenyl (and phenylcontaining moieties) and naphthyl groups and ring carbon atoms inheteroaryl (mono or bicyclic) rings in R¹¹, R¹², R^(i) and AR includehalo, (1-4C)alkyl, hydroxy, nitro, carbamoyl, (1-4C)alkylcarbamoyl,di-((1-4C)alkyl)carbamoyl, cyano, trifluoromethyl, trifluoromethoxy,amino, (1-4C)alkylamino, di((1-4-C)amino, (1-4C)alkyl S(O)_(q)—,(wherein q is 0, 1 or 2), carboxy, (1-4C)alkoxycarbonyl, (2-4C)alkenyl,(2-4C)alkynyl, (1-4C)alkanoyl, (1-4C)alkoxy, (1-4C)alkanoylamino,benzoylamino, benzoyl, phenyl (optionally substituted by up to threesubstituents selected from halo, (1-4C)alkoxy or cyano), furan, pyrrole,pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine,isoxazole, oxazole, isothiazole, thiazole, thiophene.hydroxyimino(1-4C)alkyl, (1-4C)alkoxyimino(1-4C)alkyl,hydroxy-(1-4C)alkyl, halo-(1-4C)alkyl, nitro(1-4C)alkyl,amino(1-4C)alkyl, cyano(1-4C)alkyl, (1-4C)alkanesulfonamido,aminosulfonyl, (1-4C)alkylaminosulfonyl anddi-((1-4C)alkyl)aminosulfonyl. The phenyl and naphthyl groups andheteroaryl (mono- or bicyclic) rings in R¹¹, R^(i) and AR may be mono-or disubstituted on ring carbon atoms with substituents independentlyselected from the above list of particular optional substituents.

Particular optional substituents for ring nitrogen atoms when R⁷ istetrazole, in heteroaryl groups in R¹¹, R¹² and R^(i) and AR, and in thenitrogen-containing rings in CY, which can be substituted withoutbecoming quaternised include (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyland (1-4C)alkanoyl.

Examples of halo groups include fluoro, chloro and bromo; examples of(1-4C)alkyl, include methyl, ethyl, and propyl and isopropyl; examplesof (1-6C)alkyl include methyl, ethyl, propyl, isopropyl, pentyl andhexyl; examples of (1-10C)alkyl include methyl, ethyl, propyl,isopropyl, pentyl, hexyl, heptyl, octyl and nonyl; examples of(1-4C)alkylamino include methylamino, , ethylamino and propylamino;examples of di-((1-4C)alkyl)amino include dimethylamino,N-ethyl-N-methylamino, diethylamino, N-methyl-N-propylamino anddipropylamino; examples of (1-4C)alkylS(O)_(q)— wherein q is 0, 1 or 2include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl,methylsulfonyl and ethylsulfonyl; examples of (1-4C)alkanesulfonyloxyinclude methylsulfonyloxy, ethylsulfonyloxy and propylsulfonyloxy;examples of (1-4C)alkylthio include methylthio and ethylthio; examplesof (1-4C)alkylsulfonyl include methylsulfonyl and ethylsulfonyl;examples of (1-4C)alkylaminocarbonyloxy include methylaminocarbonyloxyand ethylaminocarbonyloxy; examples of (1-4C)alkanoylamino-(1-4C)alkylinclude formamidomethyl, acetamidomethyl and acetamidoethyl; examples of(1-6C)alkoxy-(1-6C)alkyl include methoxymethyl, ethoxymethyl and2-methoxyethyl; examples of (1-4C)alkoxycarbonyl includemethoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; examples of(2-4C)alkanoyloxy include acetyloxy and propionyloxy; examples of(1-4C)alkoxy include methoxy, ethoxy and propoxy; examples of(1-6C)alkoxy include methoxy, ethoxy, propoxy and pentoxy; examples ofhydroxy-(2-6C)alkoxy include 2-hydroxyethoxy and 3-hydroxypropoxy;examples of (1-4C)alkylamino-(2-6C)alkoxy include 2-methylaminoethoxyand 2-ethylaminoethoxy; examples of di-(1-4C)alkylamino-(2-6C)alkoxyinclude 2-dimethylaminoethoxy and 2-diethylaminoethoxy; examples of(1-4C)alkoxy-(1-4C)alkoxy and (1-6C)alkoxy-(1-6)alkoxy includemethoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy and 3-methoxypropoxy;examples of (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy include2-(methoxymethoxy)ethoxy, 2-(2-methoxyethoxy)ethoxy;3-(2-methoxyethoxy)propoxy and 2-(2-ethoxyethoxy)ethoxy; examples of(1-4C)alkanoylamino and (1-6C)alkanoylamino include formamido, acetamidoand propionylamino; examples of (1-4C)alkoxycarbonylamino includemethoxycarbonylamino and ethoxycarbonylamino; examples ofN-(1-4C)alkyl-N-(2-6C)alkanoylamino include N-methylacetamido,N-ethylacetamido and N-methylpropionamido; examples of(1-4C)alkylS(O)_(p)NH— wherein p is 1 or 2 include methylsulfinylamino,methylsulfonylamino, ethylsulfinylamino and ethylsulfonylamino; examplesof (1-4C)alkylS(O)_(p)((1-4C)alkyl)NH— wherein p is 1 or 2 includemethylsulfinylmethylamino, methylsulfonylmethylamino,2-(ethylsulfinyl)ethylamino and 2-(ethylsulfonyl)ethylamino; examples offluoro(1-4)alkylS(O)_(p)NH— wherein p is 1 or 2 includetrifluoromethylsulfinylamino and trifluoromethylsulfonylamino; examplesof fluoro(1-4C)alkylS(O)_(p)((1-4C)alkyl)NH— wherein p is 1 or 2 includetrifluoromethylsulfinylmethylamino andtrifluoromethylsulfonylmethylamino examples of(1-4C)alkoxy(hydroxy)phosphoryl include methoxy(hydroxy)phosphoryl andethoxy(hydroxy)phosphoryl; examples of di-(1-4C)alkoxyphosphoryl includedi-methoxyphosphoryl, di-ethoxyphosphoryl and ethoxy(methoxy)phosphoryl;examples of 2-((1-4C)alkoxycarbonyl)ethenyl; include2-(methoxycarbonyl)ethenyl and 2-(ethoxycarbonyl)ethenyl; examples of2-cyano-2-((1-4C)alkyl)ethenyl includ 2-cyano-2-methylenyl and2-cyano-2-ethylenyl; examples of 2-(1-4C)alkylaminocarbonyl)ethenylinclude 2-(methylaminocarbonyl)ethenyl and2-(ethylaminocarbonyl)ethenyl; examples of benzyloxy(1-4C)alkyl includebenzyloxymethyl and benzyloxyethyl; examples of phenyl(1-4C)alkylinclude benzyl and phenethyl; examples of phenylS(O)_(q) wherein q is 0,1 or 2 are phenylthio, phenylsulfinyl and phenylsulfonyl respectively;examples of (1-4C)alkylcarbamoyl include methylcarbamoyl andethylcarbamoyl; examples of di((1-4C)alkyl)carbamoyl includedi(methyl)carbamoyl and di(ethyl)carbamoyl; examples of a (3-4C)alkylenechain are trimethylene or tetramethylene; examples of (2-4C)alkenylinclude allyl and vinyl; examples of (2-4C)alkynyl include ethynyl and2-propynyl; examples of (1-4C)alkanoyl include formyl, acetyl andpropionyl; examples of hydroxyimino(1-4C)alkyl includehydroxyiminomethyl, 2-(hydroxyimino)ethyl and 1-(hydroxyimino)ethyl;examples of (1-4C)alkoxyimino-(1-4C)alkyl include methoxyiminomethyl,ethoxyiminomethyl, 1-(methoxyimino)ethyl and 2-(methoxyimino)ethyl;examples of hydroxy(1-4C)alkyl and hydroxy(1-6C)alkyl includehydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl;examples of halo(1-4C)alkyl include, halomethyl, 1-haloethyl,2-haloethyl, and 3-nitropropyl; examples of nitro(1-4C)alkyl includenitromethyl, 1-nitroethyl, 2-nitroethyl and 3-nitropropyl; examples ofamino(1-4C)alkyl include aminomethyl, 1-aminoethyl, 2-aminoethyl and3-aminopropyl; examples of cyano(1-4C)alkyl include cyanomethyl,1-cyanoethyl, 2-cyanoethyl and 3-cyanopropyl; examples of(1-4C)alkanesulfonamido include methanesulfonamido andethanesulfonamido; examples of (1-4C)alkylaminosulfonyl includemethylaminosulfonyl and ethylaminosulfonyl; and examples ofdi-(1-4C)alkylaminosulfonyl include dimethylaminosulfonyl,diethylaminosulfonyl and N-methyl-N-ethylaminosulfonyl.

Suitable pharmaceutically-acceptable salts include acid addition saltssuch as methanesulfonate, fumarate, hydrochloride, hydrobromide,citrate, maleate and salts formed with phosphoric and sulfuric acid. Inanother aspect suitable salts are base salts such as an alkali metalsalt for example sodium, an alkaline earth metal salt for examplecalcium or magnesium, or organic amine salt for example triethylamine,morpholine, N-methylpiperidine, N-ethylpiperidine, procaine,dibenzylamine,N,N-dibenzylethylamine or amino acids for example lysine.There may be more than one cation or anion depending on the number ofcharged functions and the valency of the cations or anions. A preferredpharmaceutically-acceptable salt is the sodium salt.

However, to facilitate isolation of the salt during preparation, saltswhich are less soluble in the chosen solvent may be preferred whetherpharmaceutically-acceptable or not.

The compounds of the formula (I) may be administered in the form of apro-drug which is broken down in the human or animal body to give acompound of the formula (I). Examples of pro-drugs include in-vivohydrolysable esters of a compound of the formula (I).

An in-vivo hydrolysable ester of a compound of the formula (I)containing carboxy or hydroxy group is, for example, apharmaceutically-acceptable ester which is hydrolysed in the human oranimal body to produce the parent acid or alcohol. Suitablepharmaceutically-acceptable esters for carboxy include(1-6C)alkoxymethyl esters for example methoxymethyl,(1-6C)alkonoyloxymethyl esters for example pivaloyloxymethyl, phthalidylesters, (3-8C)cycloalkoxycarbonyloxy(1-6C)alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters forexample 5-methyl-1,3-dioxolen-2-onylmethyl; and(1-6C)alkoxycarbonyloxyethyl esters for example1-methoxycarbonyloxyethyl and may be formed at any carboxy group in thecompounds of this invention.

An in-vivo hydrolysable ester of a compound of the formula (I)containing a hydroxy group includes inorganic esters such as phosphateesters and α-acyloxyalkyl ethers and related compounds which as a resultof the in-vivo hydrolysis of the ester breakdown to give the parenthydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxyand 2,2-dimethylpropionyloxymethoxy. A selection of in-vivo hydrolysableester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyland substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkylcarbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl.

The compounds of the present invention have a chiral centre at the C-5position of the oxazolidinone ring. The pharmaceutically activeenantiomer is of the formula:

The present invention includes the pure enantiomer depicted above ormixtures of the 5R and 5S enantiomers, for example a racemic mixture. Ifa mixture of enantiomers is used, a larger amount (depending upon theratio of the enantiomers) will be required to achieve the same effect asthe same weight of the pharmaceutically active enantiomer. For theavoidance of doubt the enantiomer depicted above could be either 5R or5S depending upon the value of R¹. For example, when R¹ is acetamido,the enantiomer depicted above is the 5S enantiomer and when R¹ ishydroxy, the enantiomer depicted above is the 5R enantiomer.

Furthermore, some compounds of the formula (I) may have other chiralcentres, and some compounds of the formula (I) may exist as one or moreregioisomers. It is to be understood that the invention encompasses allsuch optical, diastereo- and regio-isomers that possess antibacterialactivity.

The invention relates to all tautomeric forms of the compounds of theformula (I) that possess antibacterial activity.

It is also to be understood that certain compounds of the formula (I)can exist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms which possess antibacterial activity.

In a preferred aspect of the invention there is provided a compound ofthe formula (I) as defined above, except that in the definition of R⁴and R⁵, neither R⁴ nor R⁵ can be oxo (═O).

In another aspect the present invention provides a compound of theformula (I) wherein:

R¹ is hydroxy, chloro, fluoro, (1-4C)alkanesulfonyloxy, amino, azido,(1-4C)alkoxy, (1-4C)alkythio, (1-4C)alkylaminocarbonyloxy, or of theformula —NHC(═O)R^(b) wherein R^(b) is hydrogen, (1-4C)alkoxy, amino,chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl,methylamino, dimethylamino or (1-4C)alkyl;

or R¹ is of the formula —NHS(O)_(n)(1-4C)alkyl wherein n is 0, 1 or 2;

R² and R³ are independently hydrogen or fluoro;

when D is O, R⁴ and R⁵ are independently hydrogen, hydroxy, bromo,oxo(═O), (1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl or independently asdefined for R⁷ hereinbelow;

when D is S, SO, SO₂ or NR⁷, R⁴ and R⁵ are independently hydrogen, oxo(═O), (1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl or independently asdefined for R⁷ hereinbelow;

R⁶ is hydrogen, (1-4C)alkyl, hydroxy, (1-4C)alkoxy or (2-4C)alkanoyloxy;

>A—B— is of the formula >C═C(R^(a)), >CHCHR^(a) or >C(OH)CHR^(a)—(>represent two single bonds) wherein R^(a) is hydrogen or (1-4C)alkyl;

D is O, SO, SO₂, or NR⁷;

wherein R⁷ is hydrogen, cyano, 2-((1-4C)alkoxycarbonyl)ethenyl,2-((1-4C)alkylaminocarbonyl)ethenyl, optionally substituted phenyl,optionally substituted phenyl(1-4C)alkyl, optionally substituted 5- or6-membered heteroaryl, optionally substituted naphthyl or optionallysubstituted 5/6 or 6/6 bicyclic heteroaryl ring system wherein theheteroaryl ring systems are joined to the the nitrogen by a ring carbonatom;

or R⁷ is of the formula R¹⁰CO— or R¹⁰SO₂— wherein R¹⁰ is(1-4C)alkoxycarbonyl, amino, (1-4C)alkylamino, di))1-4C)alkyl)amino or(1-6C)alkyl [wherein (1-6C)alkyl is optionally substituted by hydroxy,cyano, amino, (1-4C)alkoxy, (1-4C)alkanoyl, (1-4C)alkylamino,di((1-4C)alkyl)amino, (2-6C)alkanoylamino,N-(1-4C)alkyl-N-(2-6C)alkanoylamino, (1-4)alkylS(O)_(p)NH—,(1-4C)alkylS(O)_(p)((1-4C)alkyl)N—, phosphone,(1-4C)alkoxy(hydroxy)phoryl, di-(1-4C)alkoxyphosphoryl or(1-4C)alkylS(O)_(q) wherein p is 1 or 2 and q is 0, 1 or 2];

or R¹⁰ is of the formula R¹¹(C(O)O(1-6C)alkyl wherein R¹¹ is optionallysubstituted 5- or 6-membered heteroaryl, optionally substituted phenylor optionally substituted (1-6C)alkyl;

or R¹⁰ is of the formula R¹²O— wherein R¹² is optionally substituted(1-6C)alkyl;

or R⁷ is of the formula R^(d)OC(R^(e))═CH(C═O)—, R^(f)C(═O)C(═O)—,R^(g)N═C(R^(h))C(═O)— or R^(i)NHC(R^(j))═CHC(═))— wherein R^(d) is(1-6C)alkyl, R^(e) is hydrogen or (1-6C)alkyl or R^(d) and R^(e)together form a (3-4C)alkylene chain, R^(f) is hydrogen, (1-6C)alkyl,hydroxy(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, amino, (1-4C)alkylamino,di-(1-4C)alkylamino, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy,hydroxy(2-6C)alkoxy, (1-4C)alkylamino(2-6)alkoxy,di-(1-4C)alkylamino(2-6C)alkoxy, R^(g) is (1-6C)alkyl, hydroxy or(1-6C)alkyl, R^(h) is hydrogen or (1-6C)alkyl, R^(i) is (1-6C)alkyl,phenyl or a 5- or 6-membered heteroaryl and R^(j) is hydrogen or(1-6C)alkyl;

or R⁷ is of the formula R¹⁴CH(R¹³)(CH₂)_(m)— wherein m is 0 or 1, R¹³ isfluoro, cyano, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkoxycarbonylor hydroxy; (provided that when m is 0, R¹³ is not fluoro or hydroxy)and R¹⁴ is hydrogen or (1-4C)alkyl;

and pharmaceutically-acceptable salts thereof; except that

N-((5S)-3-(4-(2-oxo-5,6-dihydropyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-ethyl-4-(2-oxo-5,6-dihydrothiapyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamideandN-((5S)-3-(3-hydroxy-4-(2-oxo-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamideare excluded.

In a preferred aspect of the invention there is provided a compound ofthe formula (I) as defined above in the section relating to anotheraspect of the present invention, except that R⁴ is hydrogen (rather thanhydrogen or (1-4C)alkyl).

In another preferred aspect of the invention there is provided acompound of the formula (I) as defined above in the section relating toanother aspect of the present invention, except that in the definitionof R⁴ and R⁵, neither R⁴ nor R⁵ can be oxo (═O).

In a further aspect the present invention provides a compound of theformula (I) wherein:

R¹ is of the formula —NHC(═O)(1-4C)alkyl or —NHS(O)_(n)(1-4C)alkylwherein n is 0, 1 or 2;

R² and R³ are independently hydrogen or fluoro;

R⁴ and R⁵ are independently hydrogen, or methyl;

>A—B— is of the formula >C═CH,>CHCH₂ or >C(OH)CH₂—(> represents twosingle bonds) wherein R^(a) is hydrogen or (1-4C)alkyl;

D is O, S, SO, SO₂ or NR⁷;

wherein R⁷ is hydrogen, optionally substituted phenyl, optionallysubstituted phenyl(1-4C)alkyl, optionally substituted 5- or 6-memberedheteroaryl, optionally substituted naphthyl or optionally substituted5/6 or 6/6 bicyclic heteroaryl ring system wherein the heteroaryl ringsystems are joined to the the nitrogen in NR⁷ by a ring carbon atom;

or R⁷ is of the formula R¹⁰CO— or R¹⁰SO₂— wherein R¹⁰ is amino,(1-4C)alkylamino, di((1-4C)alkyl)amino or (1-6C)alkyl [wherein(1-6C)alkyl is optionally substituted by hydroxy, cyano, amino, or(1-4C)alkylS(O)_(q) wherein q is 1 or 2];

or R¹⁰ is of the formula R¹¹C(O)O(1-6C)alkyl wherein R¹¹ is optionallysubstituted 5- or 6-membered heteroaryl, optionally substituted phenylor optionally substituted (1-6C)alkyl;

or R¹⁰ is of the formula R¹²O— wherein R¹² is optionally substituted(1-6C)alkyl;

or R⁷ is of the formula R¹⁴CH(R¹³)(CH₂)_(m)— wherein m is 0 or 1, R¹³ isfluoro, cyano, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkoxycarbonylor hydroxy; (provided that when m is 0, R¹³ is not fluoro or hydroxy)and R¹⁴ is hydrogen or (1-4C)alkyl;

and pharmaceutically-acceptable salts thereof.

In the sections above relating to another aspect of the presentinvention, and to a further aspect of the present invention, ‘5- or6-membered heteroaryl’ means a 5- or 6-membered aryl ring wherein 1, 2or 3 of the ring atoms are selected from nitrogen, oxygen and sulfur.Particular examples of such 5- or 6-membered heteroaryl ring systems areimidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole,oxazole, isothiazole, thiazole and thiophene.

Also, in the sections above relating to another aspect of the presentinvention, and to a further aspect of the present invention, a ‘5/6 or6/6 bicyclic heteroaryl ring system’ means an aromatic bicyclic ringsystem comprising a 6-membered ring fused to wither a 5 membered ring oranother 6 membered ring, the bicyclic ring system containing 1 to 4heteroatoms selected from nitrogen, oxygen and sulfur. Particularexamples of 5/6 and 6/6 bicyclic ring systems are benzofuran,benzoimidazole, benzothiophene, benzisothiazole, benzoxazole,benzisoxazole, pyridoimidazole, pyrimidoimidazole, quinoline,quinoxaline, quinazoline, phthalazine, cinnoline and naphthyridine.

Particularly preferred compounds of the invention comprise a compound ofthe formula (I), or pharmaceutically-acceptable salts thereof, whereinthe substituents A, B, D, R¹ to R¹⁴ and other optional substituentsmentioned above have the values disclosed hereinbefore, or any of thefollowing values:

(a) Preferably R¹ is hydroxy, chloro, fluoro, methanesulfonyloxy, amino,azido, methoxy, methylthio, methylaminocarbonyloxy, or of the formula—NHC(═O)R^(a) wherein R^(a) is hydrogen, methoxy, amino, chloromethyl,dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl, methylamino,dimethylamino or (1-4C)alkyl or R¹ is of the formula—NHS(O)_(n)(1-4C)alkyl wherein n is 0, 1 or 2.

(b) More preferably R¹ is hydroxy, chloro, fluoro, methanesulfonyloxy,or of the formula —NHC(═O)R^(a) wherein R^(a) is hydrogen, methoxy,amino, chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl,acetylmethyl or (1-4C)alkyl or R¹ is of the formula—NHS(O)_(n)(1-4C)alkyl wherein n is 0, 1 or 2.

(c) Yet more preferably R¹ is hydroxy, or of the formula —NHC(═O)R^(a)wherein R^(a) is (1-4C)alkyl or R¹ is of the formula—NHS(O)_(n)(1-4C)alkyl wherein n is 0, 1 or 2.

(d) Yet more preferably R¹ is of the formula —NHC(═O)(1-4C)alkyl or—NHS(O)_(n)(1-4C)alkyl.

(e) Yet more preferably R¹ is of the formula —NHC(═O)(1-4C)alkyl.

(f) Most preferably R¹ is acetamido.

(g) In another aspect R¹ is hydroxy.

(h) Preferably, at least one of R² and R³ is hydrogen.

(i) Preferably R⁶ is hydrogen or (1-4C)alkyl.

(j) Most preferably one of R² and R³ is hydrogen and the other isfluoro.

(k) Preferably >A—B— is of the formula >C═CH— or >CHCH₂—.

(l) Most preferably >A—B— is of the formula >C═CH—.

(m) Preferably R⁴ and R⁵ are independently hydrogen, (1-4C)alkyl,carboxy, (1-4C)alkoxycarbonyl, hydroxymethyl, (1-4C)alkoxymethyl orcarbamoyl.

(n) More preferably, R⁴ and R⁵ are independently hydrogen, AR-oxymethylor AR-thiomethyl. Especially preferred is AR when it is optionallysubstituted phenyl, phenyl(1-4C)alkyl, naphthyl, furan, pyrrole,pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine,isoxazole, oxazole, isothiazole, thiazole or thiophene.

(o) Most preferably R⁴ or R⁵ is hydrogen.

(p) Preferably R⁶ is hydrogen or (1-4C)alkyl.

(q) More preferably R⁶ is hydrogen or methyl.

(r) Most preferably R⁶ is hydrogen.

(s) Preferably D is O, S or of the formula NR⁷.

(t) Preferably D is O.

(u) Preferred substituents for phenyl and carbon atoms in heteroaryl(mono- and bicyclic) ring systems in R⁷ and R¹¹ include halo,(1-4C)alkyl, hydroxy, nitro, amino, cyano, (1-4C)alkylS(O)_(p)— and(1-4C)alkoxy.

(v) Preferred optional substituents for (1-6C)alkyl in R¹¹ are hydroxy,cyano, amino, (1-4C)alkylamino, di((1-4C)alkyl)amino,(1-4C)alkylS(O)_(p) (wherein p is 1 or 2), carboxy,(1-4C)alkoxycarbonyl, (1-4C)alkoxy, piperazino or morpholino.

(w) Preferred optional substituents for (1-6C)alkyl in R¹² are hydroxy,(1-4C)alkoxy, cyano, amino, (1-4C)alkylamino, di(C₁₋₂alkyl)amino,(1-4C)alkylS(O)_(p)— (wherein p is 1 or 2).

(x) Preferably the ring systems in AR are unsubstituted.

(y) Preferably the 5/6 or 6/6 bicyclic ring system in R⁴, R⁵, R⁷ or R¹⁰is unsubstituted.

(z) Preferably 5- or 6-membered heteroaryl rings in R⁴, R⁵, R⁷, R¹⁰ orR¹¹ are unsubstituted.

(a1) Preferably 5- or 6-membered heteroaryl in R¹¹ is pyridyl orimidazol-1-yl.

(b1) Preferably R¹² is (1-6C)alkyl. Most preferably R¹² is tert-butyl ormethyl.

(c1) Preferably R¹³ is cyano or fluoro.

(d1) Preferably R¹⁴ is hydrogen.

(e1) Preferably R¹⁰ is (1-4C)alkoxycarbonyl, hydroxyl(1-4C)alkyl,(1-4C)alkyl, (1-4C)alkylamino, dimethylamino(1-4C)alkyl,(1-4C)alkoxymethyl, (1-4C)alkanoylmethyl, (1-4C)alkanoyloxy(1-4C)alkyl,(1-5C)alkoxy or 2-cyanoethyl.

(f1) More preferably R¹⁰ is methoxycarbonyl, hydroxymethyl, methyl,methylamino, dimethylaminomethyl, methoxymethyl, acetoxymethyl, methoxy,methylthio, naphthyl, tert-butoxy or 2-cyanoethyl.

(g1) Preferably R⁷ is hydrogen, cyano, benzyl, primidyl, imidazolyl,triazolyl or of the formula R¹⁰CO— or R¹⁰SO₂—.

(h1) Preferably R⁷ is hydrogen, cyano, benzyl, methoxycarbonyl,tert-butoxycarbonyl, hydoxyacetyl, dimethylaminoacetyl,acetyloxymethylcarbonyl, methoxyacetyl, methoxalyl, methylcarbamoyl ormethanesulfonyl.

(i1) Preferably when R¹⁰ is benzopyranone it is 4-oxo-benzopyran-2-yl.

(j1) Preferably CY is naphthoxy, especially naphth-1-oxy ornaphth-2-oxy.

Therefore, especially preferred compounds of the present invention areof the formula (IB):

wherein R¹ is hydroxy or acetamido; R² is hydrogen or fluoro and R⁴ andR⁵ are independently hydrogen, hydroxy, bromo, (1-4C)alkyl, carboxy,(1-4C)alkoxycarbonyl, hydroxymethyl, (1-4C)alkoxymethyl or carbamoyl;and pharmaceutically-acceptable salts thereof.

Of the above especially preferred compounds of the formula (IB),particularly preferred compounds are those wherein R¹ is acetamido; R²is hydrogen or fluoro and R⁴ and R⁵ are independently hydrogen, hydroxy,bromo, (1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, hydroxymethyl,(1-4C)alkoxymethyl or carbamoyl; and pharmaceutically-acceptable saltsthereof.

Further especially preferred compounds of the invention are of theformula (IB) wherein R¹ is acetamido; R² is hydrogen or fluoro and R⁴and R⁵ are independently hydrogen, AR-oxymethyl or AR-thiomethyl(wherein AR is phenyl, phenyl(1-4C)alkyl, naphthyl, furan, pyrrole,pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine,isoxazole, oxazole, isothiazole, thiazole or thiophene); andpharmaceutically-acceptable salts thereof.

Further, especially preferred compounds of the invention are of theformula (IC):

wherein R¹ is hydroxy or acetamido; R² is hydrogen or fluoro; R⁴ and R⁵are independently hydrogen, AR-oxymethyl or AR-thiomethyl (wherein AR isphenyl, phenyl(1-4C)alkyl, naphthyl, furan, pyrrole, pyrazole,imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole,oxazole, isothiazole, thiazole or thiophene), hydroxy, bromo,(1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, hydroxymethyl,(1-4C)alkoxymethyl or carbamoyl and R⁷ is cyano, pyrimidin-2-yl,tetrazol-5-yl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl or R⁷ isof the formula R¹⁰CO— or R¹⁰SO₂— (wherein R¹⁰ is hydrogen, (1-4C)alkyl[optionally substituted by hydroxy, (1-4C)alkoxy, (1-4C)alkylS(O)_(q),(1-4C)alkylamino, (1-4C)alkanoyl, naphthoxy, (2-6C)alkanoylamino or(1-4C)alkylS(O)_(p)NH— wherein p is 1 or 2 and q is 0, 1 or 2], phenyl,naphthyl, imidazole, triazole, pyrimidine, pyridazine, pyridine,isoxazole, oxazole, isothiazole, thiazole, thiophene, benzofuran,benzoimidazole, benzothiophene, benzisothiazole, benzoxazole,benzisoxazole, pyridoimidazole, pyrimidoimidazole, quinoline,quinoxaline, quinazoline, phthalazine, cinnoline or naphthyridine, orR¹⁰ is of the formula R¹¹C(O)O(1-6C)alkyl wherein R¹¹ is (1-6C)alkyl),or R⁷ is of the formula R^(f)C(═O)C(═O)— wherein R^(f) is (1-6C)alkoxy;and pharmaceutically-acceptable salts thereof.

Of the above especially preferred compounds of the invention of theformula (IC), particularly preferred compounds are those wherein R¹ isacetamido; R² is hydrogen or fluoro; R⁴ and R⁵ are independentlyhydrogen, AR-oxymethyl or AR-thiomethyl [wherein AR is phenyl,phenyl(1-4C)alkyl, naphthyl, furan, pyrrole, pyrazole, imidazole,triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole,isothiazole, thiazole or thiophene], hydroxymethyl, (1-4C)alkoxymethylor carbamoyl and R⁷ is cyano, pyrimidin-2-yl, tetrazol-5-yl,2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl, or R⁷ is of the formulaR¹⁰CO— or R¹⁰SO₂— (wherein R¹⁰ is hydrogen, (1-4C)alkyl [optionallysubstituted by hydroxy, (1-4C)alkylS(O)_(q), (1-4C)alkanoyl or naphthoxywherein q is 0, 1 or 2], phenyl, naphthyl, imidazole, trizole,pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole,thiazole, thiophene, benzofuran, benzoimidazole, benzothiphene,benzisothiazole, benzoxazole, benzisoxazole, pyridoimidazole,pyrimidoimidazole, quinoline, quinoxaline, quinazoline, phthalazine,cinnoline or naphthyridine, or R¹⁰ is of the formula R¹¹C(O)O(1-6C)alkylwherein R¹¹ is (1-6C)alkyl), or R⁷ is of the formula R^(f)C(═O)C(═O)—wherein R^(f) is (1-6C)alkoxy; and pharmaceutically-acceptable saltsthereof.

Of the above particularly preferred compounds of the invention of theformula (IC), especially preferred compounds are those wherein R¹ isacetamido; R² is hydrogen or fluoro; R⁴ and R⁵ are hydrogen and R⁷ iscyano, pyrimidin-2-yl, tetrazol-5-yl, 2-cyanoethenyl,2-cyano-2-((1-4C)alkyl)ethenyl, or R⁷ is of the formula R¹⁰CO— orR¹⁰SO₂— (wherein R¹⁰ is hydrogen, (1-4C)alkyl [optionally substituted byhydroxy, (1-4C)alkylS(O)_(q) or (1-4C)alkanoyl wherein q is 0, 1 or 2],phenyl, naphthyl, imidazole, triazole, pyrimidine, pyridazine, pyridine,isoxazole, oxazole, isothiazole, thiazole, thiophene, benzofuran,benzoimidazole, benzothiophene, benzisothiazole, benzoxazole,benzisoxazole, pyridoimidazole, pyrimidoimidazole, quinoline,quinoxaline, quinazoline, phthalazine, cinnoline or naphthyridine, orR¹⁰ is of the formula R¹¹C(O)O(1-6C)alkyl wherein R¹¹ is (1-6C)alkyl),or R⁷ is of the formula R^(f)C(═O)C(═O)— wherein R^(f) is (1-6C)alkoxy;and pharmaceutically-acceptable salts thereof.

Of the above particularly preferred compounds of the invention of theformula (IC), further especially preferred compounds are those whereinR¹ is acetamido; R² is hydrogen or fluoro; R⁴ and R⁵ are independentlyhydrogen, AR-oxymethyl or AR-thiomethyl (wherein AR is phenyl,phenyl(1-4C)alkyl, naphthyl, furan, pyrrole, pyrazole, imidazole,triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole,isothiazole, thiazole or thiophene), hydroxymethyl, (1-4C)alkoxymethylor carbamoyl and R⁷ is cyano, pyrimidin-2-yl, tetrazol-5-yl,2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl, or R⁷ is of the formulaR¹⁰CO— (wherein R¹⁰ is hydrogen, (1-4C)alkyl [optionally substituted byhydroxy, (1-4C)alkylS(O)_(q) or (1-4C)alkanoyl wherein q is 0, 1 or 2],phenyl, naphthyl, imidazole, triazole, pyrimidine, pyridazine, pyridine,isoxazole, oxazole, isothiazole, thiazole, thiophene, benzofuran,benzoimidazole, benzothiophene, benzisothiazole, benzoxazole,benzisoxazole, pyridoimidazole, pyrimidoimidazole, quinoline,quinoxaline, quinazoline, phthalazine, cinnoline or naphthyridine, orR¹⁰ is of the formula R¹¹C(O)O(1-6C)alkyl wherein R¹¹ is (1-6C)alkyl),or R⁷ is of the formula R^(f)C(═O)C(═O)— wherein R^(f) is (1-6C)alkoxy;and pharmaceutically-acceptable salts thereof.

Of the above particularly preferred compounds of the invention of theformula (IC), chiefly preferred compounds are those wherein R¹ isacetamido; R² is hydrogen or fluoro; R⁴ and R⁵ are independentlyhydrogen, AR-oxymethyl or AR-thiomethyl (wherein AR is phenyl,phenyl(1-4C)alkyl, naphthyl, furan, pyrrole, pyrazole, imidazole,triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole,isothiazole, thiazole or thiophene), hydroxymethyl, (1-4C)alkoxymethylor carbamoyl and R⁷ is cyano, pyrimidin-2-yl, tetrazol-5-yl,2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl, or R⁷ is of the formulaR¹⁰SO₂— (wherein R¹⁰ is hydrogen, (1-4C)alkyl [optionally substituted byhydroxy, (1-4C)alkylS(O)_(q) or (1-4C)alkanoyl wherein q is 0, 1 or 2],phenyl, naphthyl, imidazole, triazole, pyrimidine, pyridazine, pyridine,isoxazole, oxazole, isothiazole, thiazole, thiophene, benzofuran,benzoimidazole, benzothiophene, benzisothiazole, benzoxazole,benzisoxazole, pyridoimidazole, pyrimidoimidazole, quinoline,quinoxaline, quinazoline, phthalazine, cinnoline or naphthyridine, orR¹⁰ is of the formula R¹¹C(O)O(1-6C)alkyl wherein R¹¹ is (1-6C)alkyl),or R⁷ is of the formula R^(f)C(═O)C(═O)— wherein R^(f) is (1-6C)alkoxy;and pharmaceutically-acceptable salts thereof.

Of the above further especially preferred compounds of the invention ofthe formula (IC), particular especially preferred compounds are thosewherein R¹ is acetamido; R² is hydrogen or fluoro; R⁴ and R⁵ arehydrogen; and R⁷ is pyrimidin-2-yl, 2-cyanoethenyl,2-cyano-2-((1-4C)alkyl)ethenyl, or R⁷ is of the formula R¹⁰CO— (whereinR¹⁰ is hydrogen or (1-4C)alkyl [optionally substituted by hydroxy or(1-4C)alkylS(O)_(q) wherein q is 0, 1 or 2], or R¹⁰ is of the formulaR¹¹C(O)O(1-6C)alkyl wherein R¹¹ is (1-6C)alkyl), or R⁷ is of the formulaR^(f)C(═O)C(═O)— wherein R^(f) is (1-6C)alkoxy; andpharmaceutically-acceptable salts thereof.

Of the above chiefly preferred compounds of the invention of the formula(IC), particular chiefly preferred compounds are those wherein R¹ isacetamido; R² is hydrogen or fluoro; R⁴ and R⁵ are hydrogen; and R⁷ ispyrimidin-2-yl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl, or R⁷ isof the formula R¹⁰SO₂— (wherein R¹⁰ is hydrogen or (1-4C)alkyl[optionally substituted by hydroxy or (1-4C)alkylS(O)_(q) wherein q is0, 1 or 2], or R¹⁰ is of the formula R¹¹C(O)O(1-6C)alkyl wherein R¹¹ is(1-6C)alkyl), or R⁷ is of the formula R^(f)C(═O)C(═O)— wherein R^(f) is(1-6C)alkoxy; and pharmaceutically-acceptable salts thereof.

Of the above particular especially preferred compounds of the inventionof the formula (IC), the most preferred are those wherein R¹ isacetamido; R² is hydrogen or fluoro; R⁴ and R⁵ are hydrogen; and R⁷ ispyrimidin-2-yl, or R⁷ is of the formula R¹⁰CO— (wherein R¹⁰ is hydrogenor (1-4C)alkyl [optionally substituted by hydroxy or (1-4C)alkylS(O)_(q)wherein q is 0, 1 or 2], or R¹⁰ is of the formula R¹¹C(O)O(1-6C)alkylwherein R¹¹ is (1-6C)alkyl), or R⁷ is of the formula R^(f)C(═O)C(═O)—wherein R^(f) is (1-6C)alkoxy; and pharmaceutically-acceptable saltsthereof.

Of the above particular chiefly preferred compounds of the invention ofthe formula (IC), the most preferred are those wherein R¹ is acetamido;R² is hydrogen or fluoro; R⁴ and R⁵ are hydrogen; and R⁷ ispyrimidin-2-yl, or R⁷ is of the formula R¹⁰SO₂— (wherein R¹⁰ is hydrogenor (1-4C)alkyl [optionally substituted by hydroxy or (1-4C)alkylS(O)_(q)wherein q is 0, 1 or 2], or R¹⁰ is of the formula R¹¹C(O)O(1-6C)alkylwherein R¹¹ is (1-6C)alkyl), or R⁷ is of the formula R^(f)C(═O)C(═O)—wherein R^(f) is (1-6C)alkoxy; and pharmaceutically-acceptable saltsthereof.

Particular compounds of the present invention are:

N-((5S)-3-(4-(1-tertbutoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(1-methoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(1-methylsulfonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(1-dimethylaminoacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(2,3-dihydropyran-4-yl)-phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(2,3-dihydrothiapyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(2,3-dihydrooxothiapyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(2,3-dihydrodioxothiapyran-4-yl)phenyl-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxo-oxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(1-tertbutoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxo-5-oxazolidinylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(1-methoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(1-methylsulfonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(1-dimethylaminoacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(2,3-dihydropyran-4-yl)-phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(2,3-dihydrothiapyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(2,3-dihydrooxothiapyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(2,3-dihydrodioxothiapyrany-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(1-(pyrimidin-2-yl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(1-cyano-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(1-(acetoxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

5R-hydroxymethyl-3-(3-fluoro-4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-one;

N-((5S)-3-(3-fluoro-4-(1-(pyrimidin-2-yl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(1-cyano-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethylacetamide;

N-((5S)-3-(3-fluoro-4-(1-methoxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(1-methoxalyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(1-(N-methylcarbamoyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

and pharmaceutically-acceptable salts thereof.

Other particular compounds of the present invention are

N-((5S)-3-(4-(1-(2-cyano-2-methylethenyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(1-(hydroxymethylsulfonyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(1-(methylsulfonylaminomethylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxo-oxazolidin-5-ylmethyl)acetamide;

and pharmaceutically-acceptable salts thereof.

Particularly preferred compounds of the present invention are:

N-((5S)-3-(4-(1-methylsulfonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxo-oxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(1-acetyloxymethylcarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(-acetyloxymethylcarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(2,3-dihydro-6H-pyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(2,3-dihydro-6H-pyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(1-{pyrimid-2-yl}-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(1-methylsulfonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(1-{pyrimid-2-yl}-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(1-acetoacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(-(naphth-2-ylsulfonyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(1-(naphth-2-oxyacetyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(1-(methylthioacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

and pharmaceutically-acceptable salts thereof.

Especially preferred compounds of the invention are:

N-((5S)-3-(4-(1-methylsulfonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxo-oxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(1-acetyloxymethylcarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(1-acetyloxymethylcarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(2,3-dihydro-6H-pyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(2,3-dihydro-6H-pyran-4-yl)phenyl-2-oxooxazolidin-5-ylmethyl)acetamide;

and pharmaceutically-acceptable salts thereof.

Other especially preferred compounds of the invention are:

N-((5S)-3-(3-fluoro-4-(1-{pyrimid-2-yl}-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(1-methylsulfonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(1-{pyrimid-2-yl}-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(3-fluoro-4-(1-acetoacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(1-(naphth-2-ylsulfonyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(1-(naphth-2-oxyacetyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

N-((5S)-3-(4-(1-(methylthioacetyl)-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide;

and pharmaceutically-acceptable salts thereof.

In a further aspect the present invention provides a process forpreparing a compound of formula (I) or a pharmaceutically-acceptablesalt thereof. The compounds of formula (I) may be prepared bydeprotecting a compound of formula (II):

wherein R², R³ and R⁶ are as hereinabove defined, R¹⁸ is R⁴ or protectedR⁴, R¹⁹ is R⁵ or protected R⁵, R²⁰ is R¹ or protected R¹, >A1-B1-is >A-B- or protected >A-B- and D1 is D in which functional groups areoptionally protected; and thereafter, if necessary, forming apharmaceutically-acceptable salt.

Protecting groups may be removed by any convenient method as describedin the literature or known to the skilled chemist as appropriate for theremoval of the protecting group in question, such methods being chosenso as to effect removal of the protecting group with minimum disturbanceof groups elsewhere in the molecule.

Specific examples of protecting groups are given below for the sake ofconvenience, in which “lower” signifies that the group to which it isapplied preferably has 1-4 carbon atoms. It will be understood thatthese examples are not exhaustive. Where specific examples of methodsfor the removal of protecting groups are given below these are similarlynot exhaustive. The use of protecting groups and methods of deprotectionnot specifically mentioned is of course within the scope of theinvention.

A carboxy protecting group may be the residue of an ester-formingaliphatic or araliphatic alcohol or of an ester-forming silanol (thesaid alcohol or silanol preferably containing 1-20 carbon atoms).

Examples of carboxy protecting groups include straight or branched chain(1-12C)alkyl groups (eg isopropyl, t-butyl); lower alkoxy lower alkylgroups (eg methoxymethyl, ethoxymethyl, isobutoxymethyl; lower aliphaticacyloxy lower alkyl groups, (eg acetoxymethyl, propionyloxymethyl,butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy loweralkyl groups (eg 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl);aryl lower alkyl groups (eg p-methoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups(eg trimethylsilyl and t-butyldimethylsilyl); tri)lower alkyl)silyllower alkyl groups (eg trimethylsilylethyl); and (2-6C)alkenyl groups(eg allyl and vinylethyl).

Methods particularly appropriate for the removal of carboxyl protectinggroups include for example acid-, metal- or enzymically-catalysedhydrolysis.

Examples of hydroxy protecting groups include lower alkenyl groups (egallyl); lower alkanoyl groups (eg acetyl); lower alkoxycarbonyl groups(eg t-butoxycarbonyl); lower alkenyloxycarbonyl groups (egallyloxycarbonyl); aryl lower alkoxycarbonyl groups (egbenzoyloxycarbonyl, p-methoxybenzyloxycarbonyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri loweralkyl/arylsilyl groups (eg trimethylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl); aryl lower alkyl groups (eg benzyl) groups; andtriaryl lower alkyl groups (eg triphenylmethyl).

Examples of amino protecting groups include formyl, aralkyl groups (egbenzyl and substituted benzyl, eg p-methoxybenzyl, notrobenzyl and2,4-dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyl andfurylmethyl groups; lower alkoxycarbonyl (eg t-butoxycarbonyl); loweralkenyloxycarbonyl (eg allyloxycarbonyl); aryl lower alkoxycarbonylgroups (eg benzyloxycarbonyl, p-methoxybenzyloxycarbonyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl; trialkylsilyl (egtrimethylsilyl and t-butyldimethylsilyl); alkylidene (eg methylidene);benzylidene and substituted benzylidene groups.

Methods appropriate for removal of hydroxy and amino protecting groupsinclude, for example, acid-, metal- or enzymically-catalysed hydrolysis,for groups such as o-nitrobenzyloxycarbonyl, photolytically and forgroups such as silyl groups, fluoride.

Examples of protecting groups for amide groups include aralkoxymethyl(eg. benzyloxymethyl and substituted benzyloxymethyl); alkoxymethyl (eg.methoxymethyl and trimethylsilylethoxymethyl); tri alkyl/arylsilyl (eg.trimethylsilyl, t-butyldimethylsily, t-butyldiphenylsilyl); trialkyl/arylsilyloxymethyl (eg. t-butyldimethylsilyloxymethyl,t-butyldiphenylsilyloxymethyl); 4-alkoxyphenyl (eg. 4-methoxyphenyl);2,4-di(alkoxy)phenyl (eg. 2,4-dimethoxyphenyl); 4-alkoxybenzyl (eg.4-methoxybenzyl); 2,4-di(alkoxy)benzyl (eg. 2,4-di)methoxy)benzyl); andalk-1-enyl (eg. allyl, but-1-enyl and substituted vinyl eg.2-phenylvinyl).

Aralkoxymethyl, groups may be introduced onto the amide group byreacting the latter group with the appropriate aralkoxymethyl chloride,and removed by catalytic hydrogenation. Alkoxymethyl, trialkyl/arylsilyl and tri alkyl/silyl groups may be introduced by reactingthe amide with the appropriate chloride and removing with acid, or inthe case of the silyl containing groups fluoride ions. The alkoxyphenyland alkoxybenzyl groups are conveniently introduced by arylation oralkylation with an appropriate halide and removed by oxidation withceric ammonium nitrate. Finally alk-1-enyl groups may be introduced byreacting the amide with the appropriate aldehyde and removed with acid.

For further examples of protecting groups see one of the many generaltexts on the subject, for example, ‘Protective Groups in OrganicSynthesis’ by Theodora Green (publisher: John Wiley & Sons).

In another aspect of the present invention the compounds of the formulae(I) and (II) and pharmaceutically-acceptable salts thereof can beprepared:

(a) by modifying a substituent in or introducing a substituent intoanother compound of formula (I) or (II);

(b) when R¹ or R²⁰ is of the formula —NHS(O)_(n)(1-4C)alkyl, wherein nis 1 or 2, by oxidising a compound of the formula (I) or (II) wherein nis 0 or, when n is 2 by oxidising a compound of the formula (I) or (II)wherein n is 1;

(c) when R¹ or R²⁰ is of the formula —NHC(═O)R^(b) orNHS(O)_(n)(1-4C)alkyl, introducing the group —C(═O)R^(b) or—S(O)_(n)(1-4C)alkyl into a compound of the formula (III);

(d) when R¹ or R²⁰ is hydroxy, by reacting a compound of the formula (V)with a compound of formula (VI):

(e) when >A1-B1- is >C═CR^(a1)—, by reacting a compound of the formula(VII) with a compound of the formula (VIII):

(f) when >A1-B1- is >CHCH(R^(a1))—, by catalytic hydrogenation of acompound of the formula (I) or (II) wherein >A1-B1- is >C═CR^(a1)—;

(g) when >A1-B1- is >C═CR^(a1)—, by elimination of the elements ofwater, or HOCOR²³, or HOSO₂ R²⁴ from a compound of the formula (IX) (ie.when R²⁵ is —H, —COR²³ or —SO₂ R²⁴).

(h) when D is NR⁷ and R⁷ is R¹⁰CO— or R¹⁰S(O)_(n)—, wherein n is 2, byreaction of a compound of formula (X) with a compound of the formula(XI) or (XII), wherein n is 2:

(i) when R¹ or R²⁰ is azido, by reacting a compound of the formula(XIII) with a source of azide:

(j) when R¹ or R²⁰ is amino, by reducing a compound of the formula (I)or (II) wherein R¹ or R²⁰ is azido;

(k) when R¹ or R²⁰ is chloro, fluoro, (1-4C)alkanesulfonyloxy, or(1-4C)alkylaminocarbonyloxy, or R²⁰ is of the formula—N(CO₂R²⁷CO(1-4C)alkyl; from a compound of the formula (I) and (II)wherein R¹ or R²⁰ is hydroxy; or

(l) when R¹ R²⁰ is chloro, (1-4C)alkythio or (1-4C)alkoxy, from acompound of the formula (XIII);

wherein R², R³, R⁶ and R²⁰ are as hereinabove defined; R^(a1) is R^(a)or protected R^(a); R²¹ is (1-6C)alkyl or benzyl; R²² is of the formula(1-4C) alkyl or —S(O)_(n)(1-4C)alkyl; R²³ is (1-4C)alkyl; R²⁴ is anoptionally substituted phenyl group; R²⁵ is hydrogen, —COR²³ or —SO₂R²⁴; R²⁶ is mesyloxy or tosyloxy; R²⁷ is (1-4C)alkyl or benzyl; n is 0,1 or 2 unless otherwise stated above; L¹ is an iodo or triflate leavinggroup; L² is a leaving group, such as, for example, hydroxy or chloro;and Y is a trialkyltin residue or a boronate acid or ester residue;

and thereafter if necessary:

i) removing any protecting groups;

ii) forming a pharmaceutically-acceptable salt.

Methods for converting substituents into other substituents are known inthe art. For example an alkylthio group may be oxidised to analkylsulfinyl or alkysulfonyl group, a cyano group reduced to an aminogroup, a nitro group reduced to an amino group, a hydroxy groupalkylated to a methoxy group, a hydroxy group thiomethylated to anarylthiomethyl or a heteroarylthiomethyl group (see, for example, Tet.Lett., 585, 1972), a carbonyl group converted to a thiocarbonyl group(eg. using Lawsson's reagent) or a bromo group converted to an alkylthiogroup.

Compounds of the formula (I) or (II) wherein R¹ or R²⁰ is —NHS(O)_(n)(1-4C)alkyl can be prepared by oxidising a compound of the formula (I)or (II) with standard reagents known in the art for the oxidation of athio group to a sulfinyl or sulfonyl group. For example, a thio groupmay be oxidised to a sulfinyl group with a peracid such asm-chloroperoxybenzoic acid and oxidising agents such as potassiumpermanganate can be used to convert a thio group to a sulfonyl group.Compounds of the formula (I) or (II) wherein R¹ or R²⁰ is—NHS(1-4C)alkyl can be parepared by reacting compounds of the formula(III) with a reagent such as (1-4C)alkylSCl.

When R^(b) is (1-4C)alkyl, the group —C(═O)(1-4C)alkyl may be introducedinto a compound of the formula (III) by standard acetylation procedures.For example, the amino group may be acetylated to give an acetamidogroup using the Schotten-Baumann procedure i.e. reacting the compound ofthe formula (I) or (II) wherein R¹ or R²⁰ is amino with acetic anhydridein aqueous sodium hydroxide and THF in a temperature range of 0° C. toambient temperature. Preferably the acylation is carried out in situfollowing the catalytic hydrogenation of a compound of the formula (I)or (II) wherein R¹ or R²⁰ is azido, by performing the hydrogenation inthe presence of acetic anhydride.

When R^(b) is hydrogen, the —CHO group may be introduced into thecompound of the formula (III) by reacting the latter compound withformic acetic anhydride, in an inert organic solvent such as THF, in atemperature range of 0° C. to ambient temperature, or by reacting itwith ethyl formate in an inert organic solvent in the temperature rangeof 50-100° C.

When R^(b) is (1-4C)alkoxy, the —COO(1-4C)alkyl group may be introducedinto the compound of the formula (III) by reacting the latter compoundwith (1-4C)alkyl chloroformate, in the presence of an organic base suchas triethylamine, in an organic solvent such as dichloromethane and in atemperature range of 0° C. to ambient temperature.

When R^(b) is amino, the —CONH₂ group may be introduced into thecompound of the formula (III) by reacting the latter compound eitherwith potassium cyanate in aqueous acid (eg hydrochloric acid) in atemperature range of ambient temperature to 40° C. or with phenylcarbamate in glyme at reflux.

When R^(b) is chloromethyl, dichloromethyl, cyanomethyl ormethoxymethyl, the —C(═O)R^(b) group may be introduced into the compoundof the formula (III) by reacting the latter compound with theappropriate acid chloride under standard conditions. The acid chloridemay be prepared from the appropriate acid. When R^(b) is acetylmethyl,the —C(═O)R^(b) group may be introduced into the amino compound byreacting the latter compound with diketene, in an inert organic solventsuch as THF, in a temperature range of 0° C. to ambient temperature.

Alternatively, the compound of the formula (III) may be reacted with theappropriate acid anhydride, in dichloromethane or THF, in the presenceof an organic base such as triethylamine and in a temperature range of0° C. to ambient temperature, or the amino compound may be reacted withthe appropriate acid in the presence of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and anorganic base such as triethylamine, in an organic solvent such asdichloromethane, in a temperature range of 0° C. to ambient temperature.

When R^(b) is methylamino, the —CONHMe group may be introduced into thecompound of the formula (III) by reacting the latter compound withmethyl isocyanate in an organic solvent such as THF or acetonitrile, ina temperature range of 0° C. to ambient temperature.

When R^(b) is dimethylamino, the —CONMe₂ group may be introduced intothe compound by of the formula (III) by reacting the latter compoundwith dimethylcarbamoyl chloride and triethylamine in an organic solventsuch as THF or acetonitrile, in a temperature range of 0° C. to ambienttemperature.

Standard reaction conditions for the conversion of a compound of theformula (III) to a compound of the formula (I) or (II) wherein R¹ or R²⁰is sulfonamido are known in the art. For example, a compound of theformula (III) could be converted to a compound of the formula (I) or(II) wherein R¹ or R²⁰ is (1-4C)alkylSO₂NH— by reacting the formercompound with a sulfonyl chloride, for example, mesyl chloride, in amild base such as pyridine or triethylamine.

Alternatively compounds of the formula (I) or (II) wherein R¹ or R²⁰ is(1-4C)alkylSO₂NH— or (1-4C)alkylSONH— may be prepared by reacting acompound of the formula (III) with a compound of the formula (IV):

The compound of the formula (IV) may be prepared by oxidising a compoundof the formula (IVA):

with standard oxidising agents known for the conversion of a thio groupto a sulfinyl or sulfonyl group.

Compounds of the formula (IVA) can be prepared by reacting phthalimidewith an alkylthiochloride ((1-4C)alkylSCI).

A compound of the formula (III) may be prepared as described in process(j).

Compounds of the formulae (V) and (VI) are conveniently reacted togetherin the presence of a strong base such as butyl lithium, lithiumhexamethyldisilazide, sodium hydride, or lithium diisopropylamide. Thereaction is conveniently carried out in an inert solvent such astetrahydrofuran (THF), dimethylformamide (DMF),N,N¹-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone in atemperature range of −78° C. to −50° C. for the deprotonation andcyclisation. Suitable values for R²¹ include ethyl, butyl and benzyl andsuitable values for R²² include ethyl and n-propyl, preferably n-propyl.

A compound of the forumla (V) is conveniently prepared by reacting achloroformate of the formula (ClCOOR²¹) with a compound of the formula(VA):

wherein R²-R⁵ and >A1-B1- are as hereinabove defined. The reaction isconveniently carried out in the presence of an inorganic or organic basesuch as sodium bicarbonate or an amine base such as dimethylaniline, theformer in a solvent such as acetone/water and the latter in an organicsolvent such as THF, toluene, DMF or acetonitrile.

A compound of the formula (VA) wherein >A1-B1- is >C═CH—, may beprepared by reacting a compound of the formula (VIII) with a compound ofthe formula (VB).

The reaction between compounds of the formulae (VIII) and (VB) whereinL³ is bromo or iodo may be is carried out by treating (VB) with anorganolithium species such as 1-butyl methyl in an inert solvent such asTHF at a low temperature, such as −78° C., followed by the addition ofan anhydrous zinc halide such as zinc chloride, in a temperature rangeof 0° C. to ambient temperature, to generate the organozinc chloride(VB), wherein L¹ is ZnCl. Treatment of the organozinc chloride in situwith a compound of the formula (VIII) followed by a suitable palladium[0] catalyst such as Pd (PPh₃)₄, in the temperature range of 0° C. toambient temperature, results in the cross-coupled product (VA) afterbrief treatment with dilute acid to hydrolyse the ‘stabase’ protectedamine.

A compound of the formula (VB) may be prepared by treatment of p-iodo orp-bromoaniline with the ‘stabase’ reagent(1,2-bis(chlorodimethylsilyl)ethane) in the presence of an organic basesuch as triethylamine.

The reaction between compounds of the formulae (VII) and (VIII), whereinY is trialkyltin and L¹ is triflate is conveniently carried out in thepresence of a palladium (0) catalyst such as Pd(PPh₃)₄ or Pd(dba)₃ in atemperature range of 0-115° C. Preferably the trialkyltin group istrimethyltin. A suitable value for L¹ is iodo ortrifluoromethylsulfonyloxy.

When Y is a boronate acid or ester, the reaction may be carried outunder conditions known for the Suzuki reaction i.e. in the presence of apalladium (0) catalyst such as Pd(PPh)₃)₄ or Pd(dba)₃, in awater-miscible organic solvent such as dimethylformamide or1,2-dimethoxyethane and in the presence of a mild base such as sodiumacetate or sodium bicarbonate which is added in water. The reaction isthen heated to 80° C. Alternatively, silver oxide may be used in placeof the base, in which case the reaction may be carried out at a lowertemperature. When Y is a boronate ester, preferably L¹ is iodo. Suitableboronate esters include lower alkyl and cyclic boronate esters.

A compound of the formula (VII) wherein Y is trimethylstannyl may beprepared by methods known in the art (for example by using methodssimilar to those described in Patent Application No. WO 9413649 from acompound of the formula (VII) wherein Y is iodo or bromo). Alternativelycompounds of the formula (VII) wherein Y is a cyclic boronate ester asin (VIIA):

may be prepared from a compound of the formula (VII) wherein Y is iodoor bromo, by sequential treatment with a suitable Pd catalyst such asPdCl₂(dppf), potassium acetate and the pinacol ester of diboron in apolar solvent such as DMSO (for example see J. Org. Chem., 1995, 60,7508-7510).

A compound of the formula (VII), wherein Y is iodo may be prepared byreacting a compound of the formula (VIIB) with iodine monochloride inthe presence of trifluoroacetic acid or with iodine and silver triflate:

When Y is bromo, a compound of the formula (VII) may be prepared bybrominating a compound of the formula (VIIB) using standard brominationmethods. For example, by reacting a compound of the formula (VIIB) withN-bromosuccinimide or bromine.

A compound of the formula (VIIB) may be prepared by forming theoxazolidinone ring from the amino group of a compound of the formula(VIIC) using a similar method to that described for the preparation of acompound of the formula (I) or (II) from a compound of the formula (VA):

The resulting compound of the formula (VIIB) in which R²⁰ is hydroxy maybe converted to other compounds of the formula (VIIB) using similarmethods to those described for the formulation of a compound of theformula (I) or (II) from a compound of the formula (I) or (II) whereinR¹ or R²⁰ is hydroxy, via a compound of the formula (III).

A compound of the formula (VIII) wherein D1 is R¹⁰CON—, S or O and L¹ istriflate may be prepared by treating a compound of the formula (VIIIA)with lithium diisopropylamide in an inert solvent such as THF, at a lowtemperature, for example −78° C., followed by N-phenyl triflamide (forexample, see methods described in Synthesis, 993-95 (1991)).

Alternatively, a compound of the formula (VIII) wherein L¹ is iodo maybe prepared by treating a hydrazone of a compound of formula (VIIIA)with iodine in the presence of triethylamine (for example see methodsdetailed in Tet. Letts., 24, 1605-1608 (1983)).

Compounds of the formula (VIII) wherein D1 is R¹⁴CH(R¹³)(CH₂)_(m)—N<,aryl-N< or heteroaryl)mono or bicyclic)—N can be prepared by elaborationof the piperidone ring from the appropiate aryl- or heteroarylamine, byreaction with ethyl acrylate to give the correspondingdiethylarylimino-bb-dipropionate, which can then be cyclised underDiekmann conditions to the give corresponding piperidone b-ketoester,followed by decarboxylation with heating in acid (see methods describedin J. Chem. Soc., 5110-5118 (1962)).

Alternatively, a compound of the formula (VIII) wherein D1 isheteroaryl-N< may be prepared by reacting an appropiately substitutedheterocycle containing a leaving group such as chloro, bromo or iodowith the appropriate 4-piperidone at an elevated temperature, in aninert solvent and optionally with an acid trapping agent.

Suitable catalysts for the catalytic hydrogenation of a compound of theformula (I) or (II) wherein >A1-B1- is >C═C(R^(a1))— include Raneynickel, platinum metal or its oxide, rhodium, zinc oxide,palladium-on-charcoal and Wilkinson's catalyst (RhCl(Ph₃P)₃. Catalyichydrogenation is conveniently carried out in the temperature range 0° C.to 150° C., but preferably at ambient temperature and pressure, unlessWilkinson's catalytic is used in which case a temperature ofapproximately 50° C. and pressure of approximately 50 atmospheres arepreferable.

A compound of the formula (IX) may be prepared by reacting anintermediate of the formula (VB) with magnesium to form a Grignardreagent, or alternatively with n-butyl lithium to form a lithiatedspecies (as above), and then reacting the Grignard reagent or lithiatedspecies with a compound of formula (VIIIA). The product (VA), wherein>A1-B1- is of the formula >C(OH)CH(R^(a))— may then be elaborated aspreviously detailed for the compound of the formula (V), but withoptional protection of the hydroxyl group.

The dehydration of a compound of the formula (IX) to give a compound offormula (I) or (II) wherein >A1-B1- is of the formula >C═CR^(a1)— may becarried out using agents such as polyphosphoric acid, trifluoroaceticacid, trifluoroacetic anhydride, p-toluenesulfonic acid, sulfuric acid,thionyl chloride etc., in an inert solvent such as toluene, and atelevated temperatures. Suitable protection of the group R²⁰ may benecessary as appropriate.

A compound of the formula (I) or (II) wherein >A1-B1- is of the formula>CHCH(R^(a1))— may be prepared from a compound of the formula (I) or(II) wherein >A1-B1- is >C═CR^(a1)—, by catalytic hydrogenation, using asuitable catalyst such as palladium-on-carbon in an appropiate inert oracidic solvent such a acetic acid. Where an optically active form ofcompounds of the formula (VI) is used in previous steps, reduction ofthe >A1-B1- double bond will produce diastereoisomers which may beseparated. Where a particular diastereoisomer is of choice, a chiralasymmetry-inducing catalyst for the reduction can be used.

The reaction between a compound of the formula (X) and (XI) or (XII) isconveniently carried out under similar conditions to those described forthe acetylation or sulfonylation of a compound of the formula (III).

A compound of formula (I) or (II) wherein R¹ or R²⁰ is azido may beprepared, for example, by reacting a compound of the formula (XIII) withsodium azide in an inert solvent such as DMF in a temperature range ofambient to 100° C., normally in the region of 75° C.-85° C. A compoundof the formula (XIII) may be prepared by converting the hydroxy group ina compound of the formula (I) or (II) wherein R¹ or R²⁰ is hydroxy intoa tosyloxy or mesyloxy group by standard methods known in the art. Forexample, by reacting the compound of the formula (I) or (II) with tosylchloride or mesyl chloride in the presence of a mild base such astriethylamine, or pyridine.

Suitable reducing agents for reducing azido to amino in a compound ofthe formula (I) or (II) include triethylamine/hydrogen sulfide,triphenylphosphine or phosphite ester, or hydrogen in the presence of acatalyst. More specifically the reduction of the azido group may becarried out by heating it in an aprotic solvent, such as1,2-dimethoxyethane, in the presence of P(OMe)₃ and subsequently heatingin 6N aqueous hydrochloric acid, or reacting it with hydrogen in thepresence of palladium on carbon in a solvent such as DMF or ethylacetate. For further details on the reduction of azides to amines seeU.S. Pat. No 4,705,799. The azido compound may be reduced an convertedto a compound of the formula (I) or (II), wherein R¹ or R¹⁰ isacetamido, in situ using acetic anhydride in DMF.

A compound of the formula (I) or (II) wherein R¹ or R²⁰ is fluoro may beprepared by reacting a compound of the formula (I) or (II) wherein R¹ orR²⁰ is hydroxy (hydroxy compound) with a fluorinating agent such asdiethylaminosulfur trifluoride in an organic solvent such asdichloromethane in the temperature range of 0° C. to ambienttemperature.

When R¹ or R²⁰ is chloro, the compound of the formula (I) or (II) may beformed by reacting the hydroxy compound with a chlorinating agent. Forexample, by reacting the hydroxy compound with thionyl chloride, in atemperature range of ambient temperature to reflux, optionally in achlorinated solvent such a dichloromethane or by reacting the hydroxycompound with carbon tetrachloride/triphenyl phosphine indichloromethane, in a temperature range of 0° C. to ambient temperature.

The (1-4C)alkanesulfonyloxy compound may be prepared by reacting thehydroxy compound with (1-4C)alkanesulfonyl chloride in the presence of amild base such as triethylamine or pyridine.

The (1-4C)alkylaminocarbonyloxy compound may be prepared by reacting thehydroxy compound with (1-4C)alkyl cyanate in an organic solvent such asTHF or acetonitrile, in the presence of triethylamine, in a temperaturerange of 0° C. to 50° C.

A compound of the formula (II) wherein R²⁰ is of the formula—N(CO₂R²⁷)CO(1-4C)alkyl is conveniently prepared by reacting a compoundof the formula (I) and (II) wherein R¹ or R²⁰ is hydroxy with an amideof the formula HN(CO₂R²⁷)CO(1-4C)alkyl under Mitsunobu conditions. Forexample, in the presence of tri-n-butylphosphine and1,1′-(azodicarbonyl)dipiperidine in an organic solvent such as THF, andin the temperature range 0° C.-60° C., but preferably at ambienttemperature. Details of analogous Mitsunobu reactions are contained inTsunoda et al, Tet. Letts., 34, 1639, (1993). Amides of the formulaHN(CO₂R²⁷)CO(1-4C)alkyl may be prepared by standard procedures oforganic chemistry which are within the ordinary skill of an organicchemist.

A compound of the formula (I) or (II) wherein R¹ or R²⁰ is chloro mayalso be prepared from a compound of the formula (XIII), by reacting thelatter compound with lithium chloride and crown ether, in a suitableorganic solvent such as THF, in a temperature range of ambienttemperature to reflux. A compound of the formula (I) or (II) wherein R¹or R²⁰ is (1-4C)alkylthio or (1-4C)alkoxy may be prepared by reactingthe compound of the formula (XIII) with sodium thio(1-4C)alkoxide orsodium (1-4C)alkoxide respectively, in an alcohol or THF, in atemperature range of 0° C. to reflux.

It is also possible to convert one R⁷ group into another R⁷ group as afinal step in the preparation of a compound of the formula (I) or (II)(see the specific examples).

When an optically active form of a compound of the formula (I) isrequired, it may be obtained by carrying out one of the above proceduresusing an optically active starting material, or by resolution of aracemic form of the compound or intermediate using a standard procedure.

Similarly, when a pure regioisomer of a compound of the formula (I) isrequired, it may be obtained by carrying out one of the above proceduresusing a pure regioisomer as a starting material, or by resolution of amixture of the regioisomers or intermediates using a standard procedure.

According to a further feature of the invention there is provided acompound of the formula (I), or a pharmaceutically-acceptable saltthereof, for use in a method of treatment of the human or animal body bytherapy.

According to a further feature of the present invention there isprovided a method for producing an antibacterial effect in a warmblooded animal, such as man, in need of such treatment, which comprisesadministering to said animal an effective amount of a compound of thepresent invention, or a pharmaceutically-acceptable salt thereof.

The invention also provides a compound of the formula (I), or apharmaceutically-acceptable salt thereof, for use as a medicament; andthe use of a compound of the formula (I) of the present invention, or apharmaceutically-acceptable salt thereof, in the manufacture of a novelmedicament for use in the production of an antibacterial effect in awarm blooded animal, such as man.

In order to use a compound of the formula (I) or apharmaceutically-acceptable salt thereof for the therapeutic treatmentof mammals including humans, in particular in treating infection, it isnormally formulated in accordance with standard pharmaceutical practiceas a pharmaceutical composition.

Therefore in another aspect the present invention provides apharmaceutical composition which comprises a compound of the formula (I)or a pharmaceutically-acceptable salt thereof and apharmaceutically-acceptable diluent or carrier.

The pharmaceutical compositions of this invention may be administered instandard manner for the disease condition that it is desired to treat,for example by oral, rectal or parenteral administration. For thesepurposes the compounds of this invention may be formulated by meansknown in the art into the form of, for example, tablets, capsules,aqueous or oily solutions or suspensions, (lipid) emulsions, dispersiblepowders, suppositories, ointments, creams, drops and sterile injectableaqueous or oily solutions or suspensions.

In addition to the compounds of the present invention the pharmaceuticalcomposition of this invention may also contain or be co-administeredwith one or more known drugs selected from other clinically usefulantibacterial agents (for example β-lactams or aminoglycosides). Thesemay include penicillins, for example oxacillin or flucloxacillin andcarbapenems, for example meropenem or imipenem, to broaden thetherapeutic effectiveness against methicillin-resistant staphylococci.Compounds of this invention may also contain or be co-administered withbactericidal/permeability-increasing protein product (BPI) or effluxpump inhibitors to improve activity against gram negative bacteria andbacteria resistant to antimicrobial agents.

A suitable pharmaceutical composition of this invention is one suitablefor oral administration in unit dosage form, for example a tablet orcapsule which contains between 100 mg and 1 g of the compound of thisinvention.

In another aspect a pharmaceutical composition of the invention is onesuitable for intravenous, subcutaneous or intramuscular injection.

Each patient may receive, for example, a daily intravenous, subcutaneousor intramuscular dose of 5 mgkg-¹ to 20 mgkg-¹ of the compound of thisinvention, the composition being administered 1 to 4 times per day. Theintravenous, subcutaneous and intramuscular dose may be given by meansof a bolus injection. Alternatively the intravenous dose may be given bycontinuous infusion over a period of time. Alternatively each patientwill receive a daily oral dose which is approximately equivalent to thedaily parenteral dose, the composition being administered 1 to 4 timesper day.

Antibacterial Activity

The pharmaceutically-acceptable compounds of the present invention areuseful antibacterial agents having a good spectrum of activity in vitroagainst standard Gram-positive organisms, which are used to screen foractivity against pathogenic bacteria. Notably, thepharmaceutically-acceptable compounds of the present invention showactivity against enterococci, pneumococci and methicillin resistantstrains of S. aureus and coagulase negative staphylococci. Theantibacterial spectrum and potency of a particular compound may bedetermined in a standard test system.

The antibacterial properties of the compounds of the invention may alsobe demonstrated in-vivo in conventional tests. No overt toxicity orother untoward effects are observed when compounds of the formula I areso tested.

The following results were obtained on a standard in-vitro test system.The activity is described in terms of the minimum inhibitoryconcentration (MIC) determined by the agar-dilution technique with aninoculum size of 10⁴ CFU/spot.

Staphylococci were tested on agar, using an inoculum of 10⁴ CFU/spot andan incubation temperature of 37° C. for 24 hours—standard testconditions for the expression of methicillin resistance.

Streptococci and enterococci were tested on agar supplemented with 5%defibrinated horse blood, an inoculum of 10⁴ CFU/spot and an incubationtemperature of 37° C. in an atmosphere of 5% carbon dioxide for 48hours—blood is required for the growth of some of the test organisms.

MIC (μg/ml) Organism Example 1 Staphylococcus aureus: Oxford 1.0 Novb.Rcs 0.5 MRQS 0.5 MRQR 0.5 Coagulase Negative Staphylococcus MS 0.25 MR1.0 Streptococcus pyogenes C203 1.0 Enterococcus faecalis 1.0 Bacillussubtilis 0.25 Novb. Res = Novobiocin resistant MRQS = methicillinresistant quinolone sensitive MRQR = methicillin resistant quinoloneresistant MR = methicillin resistant MS = methicillin sensitive

The invention is now illustrated but not limited by the followingExamples in which unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solids byfiltration;

(ii) operations were carried out at ambient temperature, that is in therange 18-26° C. and in air unless otherwise stated, or unless theskilled person would otherwise work under an inert atmosphere;

(iii) column chromatography (by the flash procedure) was performed onMerck Kieselgel silica (Art. 9385) unless otherwise stated;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) the end-products of the formula I generally have satisfactorymicroanalyses and their structures were confirmed by NMR and massspectral techniques [proton magnetic resonance spectra were determinedin DMSO-D6 unless otherwise stated using a Varian Gemini 2000spectrometer operating at a field strength of 300 MHz, or a Bruker AM250spectrometer operating at a field strength of 250 MHz; chemical shiftsare reported in parts per million downfield from tetramethysilane as aninternal standard (δ scale) and peak multiplicities are shown thus: s,singlet; d, doublet; AB or dd, doublet of doublets; t, triplet, m,multiplet; fast-atom bombardment (FAB) mass spectral data were obtainedusing a Platform spectrometer (supplied by Micromas) run in electrosprayand, where appropriate, either positive ion data or negative ion datawere collected];

(vi) intermediates were not generally fully characterised and purity wasin general assessed by thin layer chromatographic, infra-red (IR), massspectral (MS) or NMR analysis; and

(vii) in which:

MPLC is medium pressure chromatography TLC is thin layer chromatographyDMSO is dimethylsulfoxide CDCl₃ is deuterated chloroform MS is massspectroscopy ESP is electrospray CI is chemical ionization DMF isN,N-dimethylformamide THF is tetrahydrofuran LDA is lithiumdiisopropylamide TFA is trifluoroacetic acid NMP is N-methylpyrrolidonedba is dibenzylideneacetone

REFERENCE EXAMPLE 1(5S)-Acetamidomethyl-3-(4-trimethyltinphenyl)oxazolidin-2-one

Hexamethyldistannane (1.77 g) followed by Pd(PPh₃)Cl₂(155 mg) was addedto a partial solution of5S-acetamidomethyl-3-(4-iodophenyl)oxazolidin-2-one (1.84 g) in dioxan(25 ml). The vessel was purged well with argon and the reaction mixturewas stirred at 95-100° C. for 6 hours, after which the reaction wasjudged as complete by TLC. The solution was decanted from a film ofblack gum which had separated, and evaporated. The title product wasisolated as an oil by MPLC (Merck 9385 silica using as eluant a mixtureof methanol and dichloromethane increasing in polarity from 5% to 10%methanol) which crystallised in 59% yield (1.19 g) on trituration withether.

See also WO Patent 94-13649 (Jun. 23, 1994) for preparation of ReferenceExample 1.

NMR (300 MHz; DMSO-D6): δ 0.25(s,9H), 1.84(s,3H), 3.42(t,2H), 3.74(d ofd,1H), 4.10(t,1H), 7.50(m,4H), 4.70(m,1H), 8.22(t,1H).

MS: ESP+(M+H)=397.

REFERENCE EXAMPLE 2N-((5S)-3-(3-Fluoro-4-(1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidine-5-ylmethyl)acetamide

Lithium chloride (1.53 g) was added to a stirred solution oft-butyl-1,2,3,6-tetrahydro-4-(trifluoromethylsulfonyloxy)pyridine-1-carboxylate(4.97 g) in NMP (50 ml), followed by Pd₂(dba)₃ (550 mg) and the vesselwas purged well with argon. After stirring for 5 minutes at ambienttemperature, a solution ofN-((5S)-3-(3-fluoro-4-trimethyltinphenyl)-2-oxooxazolidin-5-ylmethyl)acetamide(4.99 g, WO Patent 94-13649, Jun. 23, 1994) in NMP (20 ml) was added.The reaction mixture was stirred at ambient temperature for 5 hours,then at 50° C. for 18 hours. TLC (ethyl acetate) indicated that thereaction was complete. A 2.0 M aqueous potassium fluoride solution (12ml) was added and the reaction mixture stirred at ambient temperaturefor 1½ hours. Water was added and the product was extracted with ethylacetate. The organic phase was washed with water, brine, dried overanhydrous sodium sulfate and evaporated to a gum. The title compound wasisolated as a gel in 68% yield (4.39 g) by MPLC (Merck 9385 silica,using as eluant a mixture of methanol (3.5%) and dichloromethane), andused in subsequent steps without further purification.

NMR (300 MHz, DMSO-D6): δ 2.40(m, 1H), 3.40(m, 3H), 3.50(m, 1H), 3.70(m,1H), 3.98(m, 2H), 4.10(m, 1H), 4.70(m, 1H), 5.95(m, 1H), 7.35(m, 3H),8.20(t, 1H).

REFERENCE EXAMPLE 3 5,6-Dihydro-4-trifluoromethylsulfonyloxy-2H-pyran

LDA/THF (31.5 ml of 1.92 M solution) was slowly added to a stirredsolution of tetrahydro-4H-pyran-4-one (5.5 g) in THF (30 ml) at −70° C.,under argon. The mixture was stirred for 30 minutes at −70° C. and thena solution of N-phenyl triflimide (21.6 g) in THF (30 mls) was added.The mixture was allowed to warm to ambient temperature and stirred for18 hours. The reaction mixture was evaporated and subjected tochromatography by MPLC on Alumina (ICN, N32-63, using as eluant amixture of ethyl acetate (5%) and iso-hexane). The product was distilledby Kugelruhr (100° C./10 mm). Remaining traces of the triflimide reagentwere removed by a second MPLC (Silica, using as eluant a mixture ofethyl acetate (5%) and iso-hexane) followed by a second Kugelruhrdistillation, giving the title compound as a colourless oil in 40% yield(5.1 g), which was stored at −20° C.

NMR (300 MHz, CDCl₃): δ 2.24(m,2H), 3.90(m,2H), 4.25(m,2H), 5.82(m,1H).

REFERENCE EXAMPLE 41-(4-Bromo-3-fluorophenyl)-2,2,5,5-tetramethyl-1,2,5-azadisilalidine

Triethylamine (56.8 g) was added to a stirred solution of4-bromo-3-fluoroaniline (42.75 g, JCS, 2815 (1958)) in dichloromethane(400 ml) followed by the slow addition, with ice-bath cooling, of asolution of 1,2-bis(chlorodimethylsilyl)ethane (50.79 g) indichloromethane (100 ml). After stirring for 2 days, an NMR of a workedup sample showed that the reaction was complete. The reaction mixturewas washed with ice cold 2N aqueous Na₂HPO₄ and water, dried overanhydrous magnesium sulfate and evaporated to give a brown oil. Thetitle compound was isolated in 93% yield (69.4 g) by vacuumdistillation, (bp=105-110° C./0.2 bar).

NMR (300 MHz CDCl₃): δ0.22 (s, 12H), 0.85 (s, 8H), 6.52 (d of d, 1H),6.65 (d of d, 1H), 7.30 (t, 1H).

REFERENCE EXAMPLE 5 4-(1-Benzyl-4-hydroxy-4-piperidyl)-3-fluoroaniline

n-Butyllithium/hexane (129 ml of 1.40 ml) was slowly added to a stirredsolution of reference Example 4 (59.76 g) in dry THF (300 ml) at −70° C.under argon. The solution was stirred for 5 minutes, than a solution ofN-benzyl-4-piperidone (37.8 g) in THF (150 ml) was slowly added. Thereaction mixture was allowed to warm to ambient temperature and stirredfor 3 hours. The reaction mixture was then quenched by the addition ofice, followed by water, then acidified to <pH1 by the addition of 5Haqueous HCl. After stirring for 5 minutes the mixture was extracted witheither and the organic phase discarded. The aqueous phase was basifiedwith slight excess of aqueous sodium hydroxide and the product wasextracted with ether. The organic phase was washed with brine, overanhydrous sodium sulfate and evaporated to give the title compound as anoil in which crystallized on trituration with cyclohexane (yield=39.49g, 73%)

NMR (300 MHz DMSO-D6): δ1.55(d, 2H), 2.10(d of t, 2H), 2.42(m, 2H),2.55(obscured by DMSO), 3.50(s, 2H), 4.65(s, 1H), 5.18(s, 2H), 6.25(d ofd, 1H), 6.33(d of d, 1H), 7.30(m, 6H).

MS: ESP+ (M+H)=301.

REFERENCE EXAMPLE 63-Fluoro-4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)aniline

A solution of Reference Example 5 (36.0 g) in 5N aqueous HCl (200 ml)was heated under reflux for 9 hours. Concentrated HCl (50 ml) was addedand reflux was continued for a further 4 hours. The reaction mixture wasbasified, with cooling, with 40% aqueous sodium hydroxide solution andextracted with either. Addition of aqueous ammonium hydroxide solutionavoided problems with insoluble partial salts. The organic phase waswashed with brine, dried over anhydrous sodium sulfate and evaporatedwell giving the title compound as a viscous gum in 96% yield (32.33 g).

NMR (300 MHz DMSO-D6): δ2.35(s, 2H), 2.55(t, 2H), 2.98(d, 2H), 3.53(s,2H), 5.35(s, 2H), 5.75(s, 1H), 6.29(m, 2H), 6.95(t, 1H), 7.30(m, 5H).

MS: ESP+ (M+H)=283.

REFERENCE EXAMPLE 7N-Benzyloxycarbonyl-3-fluoro-4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)aniline

Dibenzyl dicarbonate (43 g) was slowly added to a stirred solution ofReference Example 6 (28.2 g) in dichloromethane (200 ml) at 0-5° C. Thereaction mixture was allowed to warm to ambient temperature and stirredfor 18 hours. The solution was evaporated to an oil which was trituratedwith ether. Sticky, insoluble material was discarded and the filtratewas purified by chromatography (MPLC on silica, using as eluant amixture of ethyl acetate (25%) and isohexane). The product was takeninto ethyl acetate and precipitated as the HCl salt by addition of amixture of HCl and ethyl acetate. The resulting product was filteredoff, washed with ethyl acetate and dried under vacuum to give the titleproduct. Yield=10.2 g (23%)

NMR (300 MHz DMSO-D6): δ2.61(m, 1H), 2.85(m, 1H), 3.20(m, 1H), 3.53(m,1H), 3.75(s, 2H), 4.40(t, 2H), 5.15(s, 2H), 5.95(s, 1H), 7.35(m, 11H),7.60(m, 2H).

MS: ESP+ (M+H)=417.

REFERENCE EXAMPLE 8N-tert-Butoxycarbonyl-N-((5R)-3-(3-fluoro-4-(N-benzyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

BOC-acetamide (2.85 g, Chem.Pharm.Bull.Jap., 36, 3125 (1988) was addedto a stirred partial solution of Example 13 (4.55 g) in dry THF (80 ml)and the mixture cooled to 0-4° C. under argon. Tributylphosphine (3.62g) was added, followed by portion-wise addition of1,1′-(azodicarbonyl)-dipiperidine (4.51 g). The reaction mixture wasstirred for 30 minutes at 0-4° C. during which time a precipitateformed. The reaction mixture was allowed to warm to ambient temperatureand stirred for 18 hours. The reaction mixture was filtered andevaporated to a gum. The title compound was rapidly isolated by MPLC(silica, using as eluant a mixture of ethyl acetate (70%) andiso-hexane) as a gum and subjected to the minimum of handling (briefevaporation at <40° C.) before deprotection in Example 12. Yield=6.9 g(inc. some solvent).

REFERENCE EXAMPLE 94-(1-tert-butyloxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluoroaniline

nBuLi (1.6M in hexanes, 33.3 ml) was added to a solution ofN,N-[1,2-bis(dimethylsilyl)ethane]-3,5-difluoroaniline (12.0 g,J.Org.chem., 60, 5255-5261 (1995)) in 150 ml THF at −70° C., maintainedtemperature below −70° C. during the addition. The mixture was thenstirred at that temperature for 4 hours. A solution of ZnCl₂ (0.5M inTHF, 106.7 ml) was then added at <60° C., the mixture allowed to warm toambient temperature and then degassed by bubbling argon through thesolution for 15 minutes. Tetrakis(triphenylphosphine) Pd⁰ (1.54 g) wasthen added together witht-butyl-1,2,5,6-tetrahydro-4-(trifluoromethylsulfonyloxy)-pyridinecarboxylate (15.4 g, Synthesis, 993 (1991)), the mixture degassed againand stirred overnight at ambient temperature. After refluxing for twohours the mixture was cooled to 10° C. and added to 100 ml ice water.After adjusting the pH to 2-3 with 5N HCl and stirring at 10° C. for 5minutes the mixture was brought to pH 8 with NaHCO₃, extracted intoethyl acetate (2×150 ml) and evaporated to give a dark oil which waschromatographed on alumina (ICN-N-32-63) with isohexane/ethyl acetate4:1. Trituration of the resulting oil gave a solid (6.62 g, 48%).

NMR(300 MHz, DMSO-D6) d: 1.46(s, 9H), 2.27(broad s, 2H), 3.52(d/d, 2H),3.97(broad s, 2H), 5.70(s, 3H), 6.20(d, 2H).

REFERENCE EXAMPLE 10N-Benzyloxycarbonyl-4-(1-tert-butyloxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluoroaniline

NaHCO₃ (5.5 g) was added to a mixture of Reference Example 9 (10.0 g),acetone (150 ml) and water (75 ml) and the mixture cooled in anice-bath. A solution of benzylchloroformate (5.3 ml) in 10 ml of acetonewas added slowly, the mixture was stirred whilst the temperature waswarmed to ambient and then stirred for a further hour. Water (100 ml)was added and the mixture extracted with ethyl acetate (100 ml+2×50 ml).The combined extracts were dried and evaporated to give a solid whichwas recrystallised from 90 ml of acetonitrile to give a solid (11.2 g).Recrystallisation of the residues gave further solid (0.73 g). Totalyield (83%).

NMR (300 MHz, DMSO-D6): 1.42(s, 9H), 2.25(broad s, 2H), 3.50(t, 2H),3.95(broad s, 2H), 5.15(s, 2H), 5.78(s, 1H), 7.15(d, 2H), 7.38(m,5H),10.16(broad s, 1H).

REFERENCE EXAMPLE 11(5R)-Hydroxymethyl-3-(3,5-difluoro-4-(tert-buryloxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-one

nBuLi (1.45M in hexanes, 15.7 ml) was added dropwise at <−70° C. to asolution of Reference Example 10 (9.65 g) in anhydrous THF (200 ml) at−70° C. After 20 minutes a solution of (R)-glycidyl butyrate (3.44 g) in25 ml THF was added at the same temperature. After the addition thecooling bath was removed and the reaction allowed to stir to ambienttemperature overnight. After addition of methanol (15 ml) and stirringfor 10 minutes, 100 ml ethyl acetate was added, the mixture cooled to10° C. and 0.5M HCl (20 ml) added slowly. After separation of theaqueous phase it was re-extracted with ethyl acetate (2×100 ml) and thecombined organic phases were washed with saturated NaHCO₃ solution, withbrine and evaporated to give an oil (12.0 g). Chomatography on silicagel with ethyl acetate gave a solid (7.66 g, 86%).

NMR (300 MHz, DMSO-D6) d: 1.40(s, 9H), 2.27(broad s, 2H), 3.51(m, 3H),3.64/3/68(m/m, 1H), 3.80(m, 1H), 3.97(broad s, 2H), 4.05(t, 1H), 4.70(m,1H), 5.18(t, 1H), 5.82(broad s, 1H), 7.32(m, 2H).

REFERENCE EXAMPLE 12 3,5-difluoro-4-(2,3-dihydropyran-4-yl)aniline

nBuLi (1.4M in hexanes, 63.5 ml) was added dropwise to a solution ofN,N-[1,2-bis(dimethylsilyl)ethane]-3,5-difluoraniline (20.0 g,J.Org.Chem., 60, 5255-5261 (1995)) in 200 ml THF at −70° C. The mixturewas stirred at that temperature for 4 hours. Chlorotitaniumtriisopropoxide (1.0M in hexanes, 89 ml) was then added dropwise at thesame temperature, and the mixture allowed to warm to ambient temperaturefor 30 minutes. The mixture was recooled to −70° C. andtetrahydro-4H-pyran-4-one (9.0 g in a few ml of THF) added dropwise andthe reaction mixture allowed to stir at ambient temperature for 48hours. After cooling in an ice bath, conc.HCl was added to pH 1-2, theorganic phase separated and the aqueous phase rextracted with ether. Theaqueous phase was adjusted to pH 9 with 2.5H NaOH, a small amount ofsolid filtered off and the filtrate extracted with ethyl acetate (4×100ml). Work-up (ie. washing and evaporation of solvent) gave an oil whichwas dissolved in 75 ml dioxan and 75 ml 5N HCl. The mixture was refluxedfor 15 minutes and the dioxan removed in vacuo. The residue was retakenup in dilute HCl, extracted with ether. The aqueous layer was basifiedto pH 8 with NaHCO₃ and extracted with ethyl acetate (3×75 ml).Evaporation in vacuo gave a solid (8.5 g, 45%).

NMR (300 MHz, DMSO-D6): 2.20(broad s, 2H), 3.74(t, 2H), 4.12(q, 2H),5.65(s, 2H), 5.70(s, 1H), 6.10(s, 1H), 6.18(s, H).

MS: ESP+ (M+H)=212.

REFERENCE EXAMPLE 13N-Benzyloxycarbonyl-4-(2,3-dihydro-6H-pyran-4-yl)-3,5-difluoroaniline

Benzylchloroformate (6.6 ml, 7.88 g) was added to a mixture of ReferenceExample 12 (8.4 g), acetone (150 ml) and water (75 ml) containing NaHCO₃(7 g) in an ice-bath. The mixture was stirred for 3 hours whilst warmingto ambient temperature. At the end of this period 100 ml water wasadded, the mixture extracted with ethyl acetate (3×100 ml) andevaporated in vacuo to give a crude solid which was triturated withether to give a solid (75%).

NMR (300 MHz, DMSO-D6) d: 2.25(broad s, 2H), 3.76(t, 2H), 4.18(m, 2H),5.15(s, 2H), 5.85(s, 1H), 7.14(s, 1H), 7.18(s, 1H), 7.38(m, 5H),10.16(broad s, 1H).

REFERENCE EXAMPLE 14(5R)-Hydroxymethyl-3-(3,5-difluoro-4-(2,3-dihydro-6H-pyran-4-yl)phenyl)oxazolidin-2-one

nBuLi (1.4M in hexanes, 23.2 ml) was added dropwise to a solution ofReference Example 13 (10.2 g) in THF (200 ml) at −70° C. and the mixturestirred for 20 minutes. A solution of (R)-glycidyl butyrate (4.68 g) inTHF (20 ml) was added dropwise and the reaction allowed to stir over 48hours, warming to ambient temperature over a few hours. Methanol (20 ml)was added, the mixture stirred for 10 minutes, then ethyl acetate (100ml) followed by 100 ml 0.5N HCl added. The organic phase was separated,the aqueous re-extracted and the combined organic phases washed withsaturated NaHCO₃ solution, followed by evaporation in vacuo to give acrude solid which was purified on silica-gel using ethyl acetate aseluant to give a solid (7.4 g, 80%).

NMR (300 MHz, DMSO-D6): 2.29(broad s, 2H), 3.53(m, 1H), 3.67(m, 1H),3.79(m, 3H), 4.06(t, 1H), 4.19(m, 2H), 4.71(m, 1H), 5.19(t, 1H), 5.89(m,1H), 7.30(s, 1H), 7.36(s, 1H).

MS: ESP+ (M+H)=312.

REFERENCE EXAMPLE 15 (2RS)-2-Methyl-4-trifluoromethylsulfonyloxy-3,6-and -5,6-dihydropyran

(RS)-2-Methyl-tetrahydro-4H-pyran-4-one (1.04 g, Chem.Ber., 88, 1053,(1955)) in dry THF (30 ml) at −78° C. was treated with LDA (2.0 M inheptane/THF/PhEt) (4.56 ml) under argon. After 45 minutesN-phenyl-bis(trifluoromethanesulfonimide) (3.58 g) was added in one goand stirring was continued for 1 hour at −78° C. The ice bath was thenremoved and stirring continued for a further 19 hours. The solution wasevaporated and the residue purified by firstly silica-gel MPLC [using amixture of 4% ethyl acetate and hexanes as eluant], and then bybulb-to-bulb distillation. Vinyl trifluoromethanesulfonate (1.36 g, 60%)as a 1.4:1 mixture of the title methyl-regioisomers was collected as thefraction at 120° C./10 mmHg.

NMR (250 MHz, CDCl₃)d: 1.29 and 1.31 (m/m, 3H each), 2.17-2.43 and2.54-2.70 (m/m, 2H each), 3.66-3.82 (m, 2H), 4.10 (ddd, 1H), 4.19-4.40(m,3H), 5.68-5.74 (m, 1H) and 5.79-5.84 (m, 1H).

REFERENCE EXAMPLE 16 2,6-dimethyl-4-hydroxy-2,3,5,6-tetrahydro-4H-pyran

2,6-Dimethyl-4H-pyran-4-one (5.0 g) in ethanol (40 ml) was hydrogenatedunder 10% Pd-C (0.5 g) at 10 bar of hydrogen for 2 days. The solutionwas then evaporated to an oil which was purified by silica-gel MPLC[using a 1:1 mixture of ethyl acetate and hexane as eluant] to give thetitle product (3.71 g, 74%).

NMR (300 MHz, CDCl₃) d: 1.16-1.25 (m,6H), 1.40-1.55 (m,2H), 1.60-1.69(m, 1H), 1.89-1.99 (m, 1H), 3.40-3.50 (m, 1H), 3.70-3.99 and 4.21 (m/m,together 2H).

REFERENCE EXAMPLE 17 2,6-dimethyl-2,3,5,6-tetrahydro-4H-pyran-4-one

Reference Example 16 (3.71 g) was dissolved in dry dichloromethane (50ml) and pyridine chlorochromate (PCC) (9.2 g) was added portionwise withstirring. The mixture was stirred for 18 hours, filtered through Celiteand evaporated. The residue was purified by bulb-to-bulb distillation(90° C., 16 mbar) to afford the title ketone (1.09 g, 30%).

NMR (300 MHz, CDCl₃) d: 1.32 (d, 6H), 2.17-2.40 (m, 4H) and 3.68-3.80(m, 2H).

REFERENCE EXAMPLE 182,6-Dimethyl-4-trifluoromethylsulfonyloxy-5,6-dihydropyran.

Reference Example 17 (1.09 g) in dry THF (10 ml) at −78° C. was treatedwith LDA (2.0 M in heptane/THF/PhEt) (5.55 ml) under argon. After 30minutes N-phenyl-bis(trifluoromethanesulfonimide) (3.21 g) was added inone go and stirring was continued for 1 hour at −78° C. The bath wasthen removed and stirring continued for a further 19 hours. The solutionwas evaporated and the residue purified by silica-gel MPLC [using amixture of 4% ethyl acetate and hexanes as eluant] to give the vinyltriflate (1.75 g, 79%).

NMR (300 MHz, CDCl₃) d: 1.50 and 1.51 (d/d, each 3H), 2.19-2.40 (m, 2H),3.70-3.83 (m, 1H), 4.30-4.40 (m, 1H) and 5.70 (s, 1H).

REFERENCE EXAMPLE 19

There is no compound with Reference Example No. 19.

REFERENCE EXAMPLE 20 2-Benzyloxymethyl-2,3,5,6-tetrahydro-4H-pyran-4-one

A mixture of (RS)-2-benzyloxymethyl-2,3-dihydro-4H-pyran-4-one (0.82 g,J. Org. Chem., 44, 811 (1979)) in ethanol (15 ml) containing 10% Pd-C(0.089 g) and triethylamine (10 drops) was hydrogenated until NMRspectroscopy indicated almost complete reaction. The solution wasevaporated and the residue purified by silica-gel MPLC [25%EtOAc/hexanes] and then bulb-to-bulb distillation [220° C./2 mmHg] togive the title ketone (0.47 g, 56%).

NMR (300 MHz, CDCl₃) d: 2.30-2.40 (m, 2H), 2.21-2.70 (m, 2H), 3.55 (d,2H), 3.70 (dt, 1H), 3.80-3.89 (m, 1H), 4.35 (dd, 1H), 4.60 (s,2H) and7.30-7.39 (m, 5H).

MS: ESP+ (M+H)=221.

REFERENCE EXAMPLE 21(2RS)-2-Benzyloxymethyl-4-trifluoromethylsulfonyloxy-3,6- and-5,6-dihydropyran

Under analogous conditions to those described in Reference Example 18,Reference Example 20 (6.1 g) was transformed into the crudevinyltriflate. Silica-gel MPLC [using a mixture of 10% ethyl acetate andhexanes as eluant], then alumina MPLC [using a mixture of 5% ethylacetate and hexanes as eluant] gave a mixture of the title products (5.9g, 61%).

NMR (300 MHz, CDCl₃) d: 2.20-2.31 (m, 2H), 2.42-2.70 (m, 2H), 2.45-3.62(m, 4H), 3.70-3.90 (m, 2H), 4.10-4.19 (m, 1H), 4.22-4.48 (m, 3H),4.52-4.63 (m, 4H), 5.79 (s, 1H), 5.80-5.82 (m, 1H) and 7.25-7.40 (m,10H).

REFERENCE EXAMPLE 22 N-((5S)-3-(4-(2-methanesulfonyloxymethyl-3,6- and-5,6-dihydropyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Mesyl chloride (0.080 g, 0.054 ml) was added slowly to a stirred mixtureof Example 52 (0.183 g), triethylamine (0.066 g, 0.090 ml) anddichloromethane (8 ml) at 0° C. After 1 hour, more mesyl chloride (0.070ml) and triethylamine (0.070 ml) were added and stirring continued for afurther 2 hours. The solution was then washed with 10% HCl, saturatedaqueous NaHCO₃ solution and with water, then dried and evaporated to anoil which was purified by Isolute silica-gel chromatography [using amixture of 6% MeOH and CH₂Cl₂ as eluant] to give a mixture of the titlemesylates (0.190 g, 85%).

NMR (300 MHz, CDCl₃) d: 2.05 (s, 3H), 2.31-2.55 (m, 1H), 2.91-3.05 (m,1H m), 3.06, 3.08 and 3.12 (s/s/s, together 3H), 3.60-4.28 (m, 6H),4.30-4.64 (m, 3H), 4.75-4.90 (m, 1H), 5.96, 6.12 and 6.30 (each broad s,together 2H) and 7.32-7.60 (m, 4 H).

MS: ESP+ (M+H)=425.

REFERENCE EXAMPLE 23 N-((5S)-3-(4-(2-azidomethyl-3,6- and5,6-dihydropyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

The mixture of mesylates Reference Example 22 (0.177 g) and sodium azide(0.041 g) in dimethyl sulfoxide (2 ml) were stirred at 80° C. for 5hours. NMR indicated very little consumption of starting material andmore sodium azide (0.050 g) was added. The mixture was heated at 80° C.for 18 hours. The resulting mixture was dissolved in ethyl acetate andwashed twice with water. The organic layer was dried and evaporated toafford the title mixture of azides (0.138 g, 89%).

NMR (300 MHz, CDCl₃) d: 2.01 and 2.05 (s/s, together 3H), 2.28-2.53 (m,2H), 3.38-3.49 (mm, 2H), 3.60-3.70 (m,. 2H), 3.78-3.90 (m, 2H), 4.09 (t,2H), 4.40-4.50 (m, 1H), 4.72-4.95 (m, 1H), 5.98 and 6.12 (s/s, together1H), 6.50 (broad t, 1H,) and 7.30-7.55 (m, 4H).

MS: ESP+ (M+H)=372.

REFERENCE EXAMPLE 24(2RS)-2-Benzyloxymethyl-4-trifluoromethylsulfonyloxy-3,6-dihydropyran

(RS)-2-Benzloxymethyl-2,3-dihydro-4H-pyran-4-one (5.69 g, J. Org. Chem.,44, 811 (1979)) in dry THF (200 ml) was treated with L-selectride (27ml, 1.0M in THF) at −78° C. and stirred for 1.25 hour.N-Phenyl-bis(tribluoromethanesulfonimaide)(10.35 g) was added andstirring continued for 3 days with warming to ambient temperature. Thesolution was evaporated to an oil which was purified by firstlysilica-gel MPLC [10% EtOAc/hexanes as eluant], then alumina MPLC [10%EtOAc/hexanes as eluant] to afford the title vinyl triflates (6.00 g,66%).

NMR (300 MHz, CDCl₃) d: 2.23 (dt, 1H), 2.41-2.58 (m, 1H), 3.50-3.62 (m,2H), 3.80-3.90 (m, 1H), 4.22-4.43 (m, 2H), 4.60 (s, 2H), 5.80 (d, 1H),7.25-7.41 (m, 5H).

EXAMPLE 1N-((5S)-3-(4-(1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

To a stirred solution oft-butyl-1,2,3,6-tetrahydro-4-(trifluoromethylsulfonyloxy)-pyridine-1-carboxylate(497 mg, Synthesis, 993 (1991)) in NMP (8 ml), was added Pd₂(dba)₃ (60mg), triphenylarsine (80 mg) and lithium chloride (166 mg), and thevessel was purged well with argon. After stirring for 5 mins. at ambienttemperature, a solution of the starting material (516 ml, ReferenceExample 1) in NMP (2 ml) was added and the reaction mixture stirred atambient temperature for 18 hours. TLC (ethyl acetate) indicatedincomplete reaction so moret-butyl-1,2,3,6-tetrahydro-4-(tribluoromethylsulfonyloxy)pyridine-1-carboxylate(497 mg) was added and the reaction mixture was heated at 40° C. for afurther 24 hours, after while the reaction was complete. A 1.0M solutionof aqueous potassium fluoride (1.0 ml) was added and the reactionmixture was stirred at ambient temperature for 30 mins. Water was addedand the product was extracted with ethyl acetate, with filtration of the2 phase mixture. The organic phase was washed with water, saturatedaqueous sodium chloride solution, dried over anhydrous sodium sulfateand evaporated to a semi-solid gum. The product was isolated by MPLC(Merck 9385 silica, using as eluant a mixture of acetonitrile and ethylacetate increasing in polarity form 0% to 50% acetonitrile over 15minutes), and was crystallised by dissolving in a small volume of ethylacetate and triturating with ether (yield=125 mg, 23%).

NMR (200 MHz, DMSO-D6): δ 1.42(s,9H), 2.43(m, obscured by DMSO),3.42(t,2H), 3.52(t,2H), 3.75(d of d, 1H), 3.98(d,2H), 4.16(t,1H),4.71(m,1H), 6.12(s,1H), 7.49(AB,4H), 8.20(t,1H).

MS: ESP+ (M+H)=416.

EXAMPLE 2N-((5S)-3-(4-(1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

A general procedure for deprotection was used as follows. The startingmaterial (Example 1) was dissolved in a small volume of trifluoroaceticacid and the yellow solution was heated briefly to reflux. Ether (10×volume of TFA used) was added, precipitating a sticky gum. The solventwas decanted off and the gum crystallised on trituration with either.The TFA salt of the product was filtered off, washed with either anddried under vacuum. For example, 10.5 mg of starting material in 0.1 mlof TFA was treated in this way to give the title compound in 97% yield(10.5 mg).

NMR (300 MHz, DMSO-D6): δ 1.81(s,3H), 2.65(s,2H), 3.35(partiallyobscured by H₂O), 3.42(t,2H), 3.75(m,3H), 4.13(t,1H), 4.73(m,1H),6.18(s,1H), 7.54(AB,4H), 8.25(t,1H), 8.85(s,2H).

MS: ESP+ (M+H)=316.

EXAMPLE 3N-((5S)-3-(4-(1-methoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxo-oxazolidin-5-ylmethyl)acetamide

To a stirred solution of the starting material (Example 2) (129 mg) in amixture of acetone (2 ml) and water (1 ml) was added sodium hydrogencarbonate (101 mg), and the mixture was cooled to 0-5° C. Methylchloroformate (34 mg, 28 μl) was added and stirring continued at 0-5° C.for 30 minutes. Then the reaction mixture was allowed to warm to ambienttemperature over 30 minutes, after which TLC (10% methanol indichloromethane) showed the reaction was complete. The reaction mixturewas diluted with water and extracted with ethyl acetate. The organicphase was washed with saturated aqueous sodium chloride solution, driedover anhydrous sodium sulfate and evaporated to give a crystalline solidwhich was recrystallised from ethyl acetate (yield=87 mg, 78%).

NMR (200 MHz, DMSO-D6): δ 1.84(s,3H), 3.42(t,2H), 3.60(t,3H),3.64(s,3H), 3.75(d of d,1H), 4.05(d,2H), 4.12(t,1H), 4.70(m,1H)6.14(s,1H), 7.47(AB,4H), 8.24(m,1H).

MS: ESP+ (M+H)=374.3.

Analysis: Calculated for C₁₉H₂₃N₃O₅: C, 61.1; H, 6.2; N, 11.1% Found: C,60.9; H, 5.9; N, 11.0%

EXAMPLE 4N-((5S)-3-(4-(1-Methylsulfonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Triethylamine (253 mg), followed by a solution of methanesulfonylchloride (69 mg) in dichloromethane (1 ml) was added, with ice-bathcooling, to a stirred suspension ofN-((5S)-3-(4-(1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide(215 mg, Example 2) in dichloromethane (10 ml). TLC showed completereaction after 2 hours. The reaction mixture was washed with 2N. HCl,water, saturated sodium hydrogen carbonate and brine. The organic phasewas dried over anhydrous sodium sulfate and evaporated to give the titlecompound as a crystalline solid which was recrystallised fromacetonitrile (yield=117 mg, 60%).

NMR (300 MHz, DMSO-D6): δ 1.80(s, 3H), 2.55(broad, 2H), 2.90(s, 3H),3.35(m, 4H), 3.73(d of d, 1H), 3.85(d, 2H), 4.10(t, 1H), 4.70(m, 1H),6.15(s, 1H), 7.48(AB, 4H), 8.21(t, 1H).

MS: ESP+ (M+H)=394.

Analysis: Calculated for C₁₈H₂₃N₃O₅S: C, 54.9; H, 5.9; N, 10.7% Found:C, 54.5; H, 5.6; N, 10.7%.

EXAMPLE 5N-((5S)-3-(4-(1-Acetyloxymethylcarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Sodium hydrogen carbonate (1.89 g) was added to a stirred solution ofExample 2 (1.92 g) in a mixture of acetone (25 ml) and water (12.5 ml),and the mixture cooled to 0-3° C. Acetoxyacetyl chloride (1.23 g, 0.97ml) was added dropwise over 5-10 mins. and the reaction mixture wasstirred at 0-5° C. for 30 minutes then allowed to warm to ambienttemperature over 1 hour. TLC (10% methanol in dichloromethane) showedcomplete reaction. The reaction mixture was diluted with water andextracted well with ethyl acetate. The organic phase was washed withbrine and dried over anhydrous sodium sulfate. The title compoundcrystallized during evaporation of the solvent and was triturated witheither (yield=1.70 g, 91%).

NMR (300 MHz, DMSO-D6): δ 1.81((s, 3H), 2.08(s, 3H), 2.5(obscured byDMSO), 3.40(t, 2H), 3.55(t, 1H), 3.65(t, 1H), 3.75(d of d, 1H), 4.10(m,3H), 4.70(m, 1H), 4.85(d, 2H), 6.15(s, 1H), 7.48(m, 4H), 8.20(t, 1H).

MS: ESP+ (M+H)=416.

EXAMPLE 6N-((5S)-3-(4-(1-Hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Example 5 (1.70 g) was stirred at ambient temperature with saturatedmethanolic ammonia (20 ml) for 18 hours. The initial suspension gave asolution after several hours from which the product crystallized. TLCshowed complete reaction. The title compound was filtered off and washedwith a little methanol (yield=1.28 g, 84%).

NMR (300 MHz, DMSO-D6): δ 1.81(s, 3H), 2.5(obscured by DMSO), 3.39(t,2H), 3.50(m, 1H), 3.72(m, 2H), 4.10(m, 5H), 4.55(d, 1H), 4.70(m, 1H),6.15(d, 1H), 7.45(m, 4H), 8.21(t, 1H).

MS: ESP+ (M+H)=374.

Analysis: Calculated for C₁₉H₂₃N₃O₅: C, 61.1; H, 6.2; N, 11.3% Found: C,60.8; H, 6.3; N, 11.1%.

EXAMPLE 7N-((5S)-3-(3-Fluoro-4-(1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Reference Example 2 (4.1 g) was dissolved in TFA (10 ml) and the yellowsolution was heated briefly to reflux. The bulk of the TFA wasevaporated and the residue was triturated with ether, precipitatinginitially a sticky gum which solidified to a yellow powder. The titlecompound was obtained by filtration as a TFA salt, washed with ether anddried under vacuum (yield=2.64 g, 62%).

NMR (300 MHz, DMSO-D6): δ 1.84(s, 3H), 2.65(s, 2H), 3.40(m, partiallyobscured by H₂O, 4H), 3.75(m, 3H), 4.10(t, 1H), 4.75(m, 1H), 6.05(m,1H), 7.42(m, 3H), 8.25(t, 1H), 8.85(s, 2H).

EXAMPLE 8N-((5S)-3-(3-Fluoro-4-(1-acetyloxymethylcarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

The title compound was prepared using a similar method to thatdescribing the preparation of Example 5, except using Example 7 as thestarting material (2.41 g). Yield=2.2 g, 94%.

NMR (300 MHz, DMSO-D6): δ 1.82(s, 3H), 2.10(s, 3H), 2.42(s, 2H), 3.40(m,2H), 3.55(m, 1H), 3.62(m, 1H), 3.72(m, 1H), 4.10(m, 3H), 4.72(m, 1H),4.82(d, 2H), 6.0(m, 1H), 7.38(m, 3H), 8.21(t, 1H).

MS: ESP+ (M+H)=434.

EXAMPLE 9N-((5S)-3-(3-Fluoro-4-(1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

The title compound was prepared using a similar method to thatdescribing the preparation of Example 6, except using Example 8 as thestarting material (1.92 g). Yield=1.25 g, 72%.

NMR (300 MHz, DMSO-D6): δ 1.80(s, 3H), 2.45(obscured by DMSO), 3.52(t,1H), 3.65(t, 1H), 3.75(d of d, 1H), 4.10(m, 5H), 4.55(d, 1H), 4.70(m,1H), 6.00(d, 1H), 7.24(d of d, 1H), 7.40(t, 1H), 7.47(d, 1H), 8.2(t,1H).

MS: ESP+ (M+H)=392.

EXAMPLE 10N-((5S)-3-(4-(2,3-Dihydro-6H-pyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Triphenylarsine (61 mg), Pd₂(dba)₃ (45.8 mg) and lithium chloride (128mg) were added to a stirred solution of Reference Example 3 (278 mg) inNMP (5 ml) and the vessel was purged well with argon. After stirring for5 minutes at ambient temperature, Reference Example 1 (397 mg) was addedand the reaction mixture was stirred at 40° C. for 24 hours. TLC (ethylacetate) indicated complete reaction. A 2.0M aqueous potassium fluoridesolution (1 ml) was added and the reaction mixture was stirred atambient temperature for 30 minutes. Water was added and the product wasextracted with ethyl acetate, with filtration of the two phase mixture.The organic phase was washed with water, brine, dried over anhydroussodium sulfate and evaporated to a gum. The title compound was isolatedby MPLC (Merck 9385 silica, using as eluant a mixture of acetonitrile(40%) and ethyl acetate), and was triturated with ether giving acrystalline powder (yield=104 mg, 33%).

NMR (300 MHz, DMSO-D6): δ 1.83(t, 3H), 2.42(s, 2H), 3.40(m, 2H), 3.73(m,1H), 3.80(t,2H), 4.10(t, 1H), 4.20(d, 2H), 4.70(m, 1H), 6.22(s, 1H),7.47(AB, 4H), 8.23(t, 1H).

MS: ESP+ (M+H)=317.

EXAMPLE 11N-((5S)-3-(3-Fluoro-4-(2,3-dihydro-6H-pyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

The title compound was prepared using a similar method to thatdescribing the preparation of Example 10, except thatN-((5S)-3-(3-fluoro-4-trimethyltinphenyl)-2-oxooxazolidin-5-ylmethyl)acetamide(415 mg, WO Patent 94-13649, Jun. 6, 1994) was used as the startingmaterial and a reaction time of 2 days was required. Yield=130 mg, 39%.

NMR (300 MHz, DMSO-D6): δ 1.82(t, 3H), 2.40(s, 2H), 3.40(s, 2H), 3.40(m,2H), 3.71(d of d, 1H), 3.80(t, 2H), 4.10(t, 1H), 4.20(d, 2H), 4.73(m,1H), 6.08(s, 1H), 7.28(d of d, 1H), 7.38(t, 1H), 7.47(d of d, 1H),8.21(t, 1H).

MS: ESP+ (M+H)=335.

EXAMPLE 12N-((5S)-3-(3-Fluoro-4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Reference Example 8 (6.9 g) was dissolved in TFA (10 ml) and heatedbriefly to reflux. The TFA was evaporated and the residue was basifiedwith aqueous ammonium hydroxide solution and the product extracted withethyl acetate. The organic phase was dried over anhydrous magnesiumsulfate and evaporated to an oil which crystallized on trituration withether to give the title compound (yield=3.78 g, 75% over 2 stages).

NMR (300 MHz, DMSO-D6): δ 1.81(s, 3H), 2.41(s, 2H), 2.60(m, 2H), 3.05(s,2H), 3.40(m, 2H), 3.58(s, 2H), 3.72(m, 1H), 4.10(m, 1H), 4.70(m, 1H),5.95(s, 1H), 7.31(m, 10H), 8.20(t, 1H).

MS: ESP+ (M+H)=424.

EXAMPLE 13(5R)-Hydroxymethyl-3-(3-fluoro-4-(N-benzyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-one

n-Buryllithium/hexane (28.1 ml of 1.40M) was slowly added to a stirredpartial solution of Reference Example 7 (8.7 g) in dry THF (100 ml) at−70° C. under argon. The solution was stirred for 15 minutes, then asolution of R-glycidyl butyrate (3.04 g) in THF (15 ml) was added andthe reaction mixture was allowed to warm to ambient temperature andstirred for 18 hours. The reaction mixture was quenched with water andextracted with ethyl acetate. The organic phase was washed with water,brine, dried over anhydrous sodium sulfate and evaporated to give thetitle compound as a gum which was isolated by MPLC (silica, using aseluant a mixture of methanol (5%) and dichloromethane) andrecrystallised from acetonitrile. Yield=4.78 g, 58%.

NMR (300 MHz, DMSO-D6): δ 2.43(s, 2H), 2.60(m, 2H), 3.05(s, 2H), 3.53(m,1H), 3.58(s, 2H), 3.65(m, 1H), 3.80(d of d, 1H), 4.07(m, 1H), 5.19(t,1H), 5.95(s, 1H), 7.30(m, 7H), 7.47(d of d, 1H).

MS: ESP+ (M+H)=383.

Analysis: Calculated for C₂₂H₂₃N₂O₃F: C, 69.0; H, 6.0; N, 7.3% Found: C,69.2; H, 6.1; N, 7.4%.

EXAMPLE 14N-((5S)-3(3-Fluoro-4-(1-methoxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

A solution of the hydrochloride salt of Example 7 (300 mg) and NaHCO₃(340 mg) in acetone (8 ml)/water (4 ml) was cooled to 0-4° C. andmethoxyacetyl chloride (176 mg) was added dropwise. After stirring for15 minutes additional NaHCO₃ and methoxyacetyl chloride (as above) wereadded giving complete reaction within 10 minutes. The reaction mixturewas diluted with water and extracted with ethyl acetate. The organicphase was washed with saturated NaCl solution, dried over anhydrousNa₂SO₄ and evaporated to a gum. The title compound was isolated by MPLC(4% MeOH/CH₂Cl₂, Merck 9385 silica), and was triturated with ether(yield=236 mg, 72%).

NMR (300 MHz, DMSO-D6) δ: 1.80(s, 3H), 2.4(broad, 2H), 3.27(s,3H+water), 3.38(t, 2H), 3.52(broad, 1H), 3.62(broad, 1H), 3.71(q, 1H),4.18(m, 5H), 4.70(m, 1H), 5.97(s, 1H), 7.25(d of d, 1H), 7.35(t, 1H),7.45(d of d, 1H), 8.19(t, 1H).

MS: ESP+(M+H)=406.

The hydrochloride salt of Example 7 was prepared by the reaction in drydichloromethane at 0-4° C. of Example 12 (16.6 g) with 1-chloroethylchloroformate (6.73 g, added dropwise), in the presence of triethylamine(0.59 g). After reaction for 0.5 hours the solvent was removed undervacuum and the residue refluxed with methanol (100 ml) for 0.5 hours.The methanol was removed under vacuum and the residue recrystallisedfrom ethanol (250 ml) to yield the hydrochloride salt of Example 7(11.92 g, 82%, NMR as previously assigned for Example 7).

EXAMPLE 15N-((5S)-3-(3-Fluoro-4-(1-methyloxalyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

The hydrochloride salt of Example 7 (300 mg) was suspended in ethylacetate, washed with aqueous ammonia, dried over anhydrous Na₂SO₄ andevaporated to give the free base of Example 7. Triethylamine (152 mg)was added to a mixture of the resulting free base of Example 7 indichloromethane (10 ml), followed by the addition of methyloxalylchloride (123 mg). Reaction was complete after 10 minutes. The reactionmixture was washed with 2N HCl, water, aqueous ammonia and saturatedNaCl. The organic phase was dried over anhydrous Na₂SO₄ and evaporatedto a gum. The title compound was isolated by MPLC (4% MeOH/CH₂Cl₂, Merck9385 silica), and was triturated with ether (yield=181 mg, 53%).

NMR (300 MHz, DMSO-D6) δ: 1.79 (s, 1H), 2.50 (obscured by solvent), 3.38(t, 2H), 3.55 (t, 1H), 3.70 (m, 2), 3.82 (d, 3H), 4.05 (s, 1H), 4.12 (m,2H), 4.70 (m, 1H), 5.98 (d, 1H), 7.25 (d of d, 1H), 7.35 (t, 1H), 7.45(d of d, 1H), 8.19 (t, 1H).

MS: ESP+ (M+H)=420.

EXAMPLE 16N-((5S)-3-(3-Fluoro-4-(-ethylaminocarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Triethylamine (101 mg), followed by ethyl isocyanate (71 mg) were addedto a stirred suspension of the hydrochloride salt of Example 7 (300 mg)in THF (10 ml). After stirring for 2 hours, additional triethylamine andethyl isocyanate (as above) were added, giving complete reaction after 3days at ambient temperature. The reaction mixture was washed with 2NHCl, water, saturated NaHCO₃ solution and saturated NaCl solution.Crystallised product was filtered off. The organic phase was dried overanhydrous Na₂SO₄ and evaporated to give a crystalline solid. Thecombined product was purified by MPLC (using a mixture of methanol anddichloromethane of increasing polarity as eluant, Merck 9385 silica),and was triturated with ether to give the title compound (222 mg, 68%).

NMR (300 MHz, DMSO-D6)δ: 1.00 (t, 3H), 1.80 (s, 3H), 2.37 (broad, 2H),3.05 (6 line, 2H), 3.38 (t, 2H), 3.47 (t, 2H), 3.71 (q, 1H), 3.92(broad, 2H), 4.10 (t, 1H), 4.70 (t, 1H), 5.98 (s, 1H), 6.72 (m, 1H),7.25 (d of d, 1H), 7.35 (t, 1H), 7.45 (d of d, 1H), 8.20 (t, 1H).

MS: ESP+(M+H)=405.

EXAMPLE 17N-((5S)-3-(3-Fluoro-4-(1-acetoacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Triethylamine (202 mg), followed by diketene (227 mg) were added to astirred suspension of the hydrochloride salt of Example 7 (665 mg) indichloromethane (15 ml). The starting material dissolved and aprecipitate of product began to separate after 15 minutes. The reactionwas complete after 30 minutes. The precipitate was filtered off, washedwith dichloromethane and recrystallised form acetonitrile to give thetitle compound (520 mg, 69%).

NMR (300 MHz, DMSO-D6) δ: 1.81 (s, 3H), 2.15 (d, 3H), 2.40 (broad, 2H),3.39 (t, 2H), 3.50 (t, 1H), 3.70 (m, 4H), 4.10 (m, 3H), 4.72 (m, 1H),5.98 (d, 1H), 7.25 (d of d, 1H), 7.38 (t of d, 1H), 7.45 (d, 1H), 8.20(t, 1H).

MS: ESP+(M+H)=418.

EXAMPLE 18N-((5S)-3-(3-Fluoro-4-(1-(2-{2-methoxyethoxy}ethoxy)methylcarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

N-Methylmorpholine (101 mg), 2-[2-(2-methoxyethoxy)ethoxy]acetic acid(154 mg) and N-hydroxybenzotriazole (122 mg, allowing for 5% water) wereadded to a mixture of the hydrochloride salt of Example 7 (277 mg) andDMF (5 ml). The mixture was stirred for 5 minutes at ambient temperatureand then 1-ethyl-3-dimethylaminopropyl-carbodiimide (165 mg) was addedand the mixture stirred for 18 hours. The solvent was evaporated underhigh vacuum and the residue partially purified by MPLC [using a mixtureof methanol and dichloromethane increasing in polarity from 5% to 25%methanol as eluant, Merck 9385 silica]. Final purification byreverse-phase MPLC [using a mixture of acetonitrile and water,increasing in acetonitrile from 0% to 25% as eluant, HP20SS resin] andtrituration with ether gave the title compound (111 mg, 30%).

NMR (300 MHz, DMSO-D6) d: 1.80 (s, 1H), 1.86 (s, 1H), 2.43 (partiallyobscured), 3.20 (s, 2H), 3.40 (m, 3H), 3.55 (m, 10H), 3.72 (m, 1H), 4.08(m, 3H), 4.20 (s, 2H), 4.70 (m, 1H), 6.00 (s, 1H), 7.26 (d, 1H), 7.35(t, 1H), 7.45 (d, 1H), 8.20 (t, 1H).

MS: ESP+(M+H)=494.

EXAMPLE 19N-((5S)-3-(3-Fluoro-4-(1-formyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

In an analogous manner to that described in Example 15, thehydrochloride salt of Example 7 (370 mg) was converted to the free base,which was then refluxed with ethyl formate (25 ml) for 24 hours. Thereaction mixture was evaporated and the title compound was isolated byMPLC (5% MeOH/CH₂Cl₂ eluant, Merck 9385 silica). The title productcrystallised on trituration with ether (297 mg, 82%).

NMR (300 MHz, DMSO-D6) δ: 1.80 (s, 1H), 2.43 (m, 2H), 3.40 (t, 2H), 3.58(m, 2H), 3.72 (q, 1H), 4.02 (d, 1H), 4.07 (s, 1H), 4.11 (t, 1H), 4.72(m, 1H), 5.98 (d, 1H), 7.25 (d of d, 1H), 7.35 (t, 1H), 7.45 (d of d,1H), 8.12 (d, 1H), 8.20 (t, 1H).

MS: ESP+(M+H)=362.

EXAMPLE 20N-((5S)-3-(3-Fluoro-4-(1acetylaminoacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

N-Methylmorpholine (101 mg), N-acetylglycine (101 mg) andN-hydroxybenzotriazole (122 mg, allowing for 5% water) were added to amixture of the hydrochloride salt of Example 7 (277 mg) and DMF (5 ml).The mixture was stirred for 5 minutes at ambient temperature then1-ethyl-3-dimethylaminopropyl-carbodiimide (165 mg) was added and themixture was stirred for 18 hours. The solvent was evaporated under highvacuum and the title compound was isolated by MPLC (using a mixture ofmethanol and dichloromethane increasing in polarity from 4-10% methanolas eluant, Merck 9385 silica). The title product crystallised ontrituration with ether (270 mg, 83%).

NMR (300 MHz, DMSO-D6)δ: 1.80 (s, 1H), 1.86 (s, 1H), 2.45 (partiallyobscured), 3.39 (t, 2H), 3.60 (m, 2H), 3.72 (q, 1H), 3.95 (d of d, 2H),4.10 (m, 3H), 4.72 (m, 1H), 5.99 (broad, 1H), 7.25 (d of d, 1H), 7.38 (tof d, 1H), 7.45 (d, 1H), 7.96 (broad, 1H), 8.20 (t, 1H).

MS: ESP+(M+H)=433.

EXAMPLE 21N-((5S)-3-(3-Fluoro-4-(-acetylacetoxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

4-Dimethylaminopyridine (4 mg) followed by diketene (118 mg) were addedto a stirred solution of the Example 9 (261 mg) in dry dichloromethane(10 ml). After stirring for 30 minutes at ambient temperature thereaction mixture was evaporated and the title compound was isolated byMPLC (5% MeOH/CH₂Cl₂ eluant, Merck 9385 silica). The title productcrystallised on trituration with ether (255 mg, 80%).

NMR (300 MHz, DMSO-D6)δ: 1.80 (s, 3H), 2.22 (s, 3H), 2.50 (obscured),3.40 (t, 2H), 3.55 (t, 1H), 3.64 (s, 3H), 3.73 (q, 1H), 4.07 (m, 3H),4.68 (m, 1H), 4.87 (d, 2H), 6.13 (broad, 1H), 7.46 (m, 4H), 8.20 (t,1H).

MS: ESP+(M+H)=458.

EXAMPLE 22N-((5S)-3-(3-Fluoro-4-(1-(2-methyl-2-phenylamino)ethenylcarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

A mixture of Example 17 (104 mg), aniline (47 mg), p-toluenesulfonicacid (p-TSA) (5 mg) and ethanol (ca. 10 ml) was stirred under reflux for24 hours. Additional aniline (233 mg) and p-TSA (5 mg) were added,together with 3A molecular sieve powder (1 g) and reflux continued for afurther 24 hours. The reaction mixture was filtered, evaporated. MPLC[using a mixture of acetonitrile and ethyl acetate, increasing inacetonitrile from 25% to 50% as eluant], and trituration with ether gavethe title compound (43 mg, 35%).

NMR (300 MHz, DMSO-D6) d: 1.82 (s, 3H), 2.05 (s, 3H), 2.45 (obscured),3.40 (q, 2H), 3.70 (m, 3H), 4.14 (m, 3H), 4.72 (m, 1H), 5.08 (s, 1H),6.04 (s, 1H), 7.10 (m, 3H), 7.37 (m, 5H), 8.20 (t, 1H), 11.67 (s, 1H).

MS: ESP+(M+H)=493.

EXAMPLE 23

There is no compound with Example No. 23.

EXAMPLE 24N-((5S)-3-(3-fluoro-4-(1-cyano-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

4-Dimethylaminopyridine (24 mg), triethylamine (606 mg) and a solutionof cyanogen bromide (1.06 g) in dichloromethane (5 ml) were added to astirred suspension of the hydrochloride salt of Example 7 (739 mg) indry dichloromethane (15 ml). After stirring for 1 hour at ambienttemperature, a solution had formed and the reaction was complete. Thereaction mixture was washed with 2N HCl, aqueous NaHCO₃ and dried overanhydrous Na₂SO₄. The mixture was evaporated to give a gum whichcrystallised on trituration with ether (488 mg, 68%).

NMR (300 MHz, DMSO-D6) δ: 1.81 (s, 3H), 2.50 (d, obscured), 3.39 (t,4H), 3.71 (q, 1H), 3.92 (d, 2H), 4.11 (t, 1H), 4.72 (m, 1H), 5.95 (s,1H), 7.27 (d of d, 1H), 7.35 (t, 1H), 7.47 (d of d, 1H), 8.20 (t, 1H).

MS: ESP+(M+H)=359.

EXAMPLE 25N-((5S)-3-(3-Fluoro-4-(1-{pyrimid-2-yl}-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

A stirred mixture of the hydrochloride salt of Example 7 (1.29 g),NaHCO₃ (1.18 g) and 2-chloropyrimidine (601 mg) was heated under refluxfor 5 hours. The solvent was evaporated and the residue was taken intoethyl acetate and washed with water and brine. The organic phase wasdried over anhydrous Na₂SO₄ and evaporated. The title compound wasisolated by MPLC (using a mixture of acetonitrile and ethyl acetateincreasing in polarity from 50% to 65% acetonitrile as eluant, Merck9385 silica), and was triturated with ether (939 mg, 65%).

NMR (300 MHz, DMSO-D6)δ: 1.82 (s, 3H), 2.50 (obscured), 3.40 (t, 2H),3.70 (q, 1H), 3.95 (t, 2H), 4.10 (t, 1H), 4.30 (q, 2H), 4.70 (m, 1H),6.10 (s, 1H), 6.62 (t, 1H), 7.27 (d of d, 1H), 7.39 (t, 1H), 7.47 (d ofd, 1H), 8.20 (t, 1H), 8.37 (d, 2H).

MS: ESP+(M+H)=412.

EXAMPLE 26N-((5S)-3-(3-Fluoro-4-(1-{tetrazol-5-yl}-1,2,5,6-tetrahydropyrid-4-yl)phenyl-2-oxooxazolidin-5-ylmethyl)acetamide

Azidotrimethylsilane (154 mg) and dibutyltin oxide (97 mg) were added toa stirred suspension of Example 24 (240 mg) in dry toluene (10 ml), andthe mixture stirred at 70° C. for 18 hours. On cooling, methanol (5 ml)was added and after stirring for 10 minutes the solvent was evaporated.The title compound was isolated by MPLC (20% MeOH/CH₂Cl₂, Merck 9385silica) and crystallised on evaporating the fractions to a small volume.The title product was filtered off washed with a little cold methanol(150 mg, 56%).

NMR (300 MHz, DMSO-D6) δ: 1.80 (s, 3H), 2.55 (s, 2H), 3.30 (obscured,1H), 3.39 (t, 2H), 3.63 (t, 2H), 3.73 (q, 1H), 4.05 (d, 2H), 4.12 (t,1H), 4.62 (m, 1H), 6.08 (s, 1H), 7.27 (d of d, 1H), 7.39 (t, 1H), 7.47(d of d, 1H), 8.19 (t, 1H).

MS: ESP+(M+H)=402.

EXAMPLE 27

There is no compound with Example No. 27.

EXAMPLE 28

There is no compound with Example No. 28.

EXAMPLE 29N-((5S)-3-(3-Fluoro-4-(1-methylsulfonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Triethylamine (242 mg), followed by methanesulfonyl chloride (115 mg)were added to a stirred suspension of the hydrochloride salt of Example7 (296 mg) in dichloromethane (10 ml). After stirring for 30 minutes,additional triethylamine and methanesulfonyl chloride (as above) wereadded giving a solution, and complete reaction after a further 30minutes at ambient temperature. The reaction mixture was washed with 2NHCl, water, saturated NaHCO₃ and saturated NaCl. The organic phase wasdried over anhydrous Na₂SO₄ and evaporated to give a crystalline solid.This was purified by MPLC (using 5% MeOH/CH₂Cl₂ as eluant, Merck 9385silica) and triturated with ether to give the title compound (209 mg,64%).

NMR (300 MHz, DMSO-D6)δ: 1.80 (s, 3H), 2.55 (s, 2H), 2.93 (s, 3H), 3.35(m, 4H), 3.72 (q, 1H), 3.85 (d, 2H), 4.11 (t, 1H), 4.72 (m, 1H), 6.02(s, 1H), 7.27 (d of d, 1H), 7.39 (t, 1H), 7.47 (d of d, 1H), 8.20 (t,1H).

MS: ESP+(M+H)=412.

EXAMPLE 30N-((5S)-3-(4-(1-Decyloxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Sodium hydride (29 mg, 60% in mineral oil) was added to a stirredsolution of Example 6 (242 mg) in dry DMF (5 ml). There was aneffervescence and a precipitate formed. After 5 minutes, decyl iodide(209 mg) was added and the reaction mixture was stirred for 24 hours atambient temperature. Additional sodium hydride and decyl iodide (asabove) were added giving almost complete reaction after a further 24hours. The reaction mixture was diluted with water and extracted withethyl acetate. The organic phase was washed with water and saturatedNaCl, was dried over anhydrous Na₂SO₄ and evaporated to give a gum. Thetitle compound was isolated by MPLC (using 3.5% MeOH/CH₂Cl₂ as eluant,Merck 9385 silica), and was triturated with ether. Yield=132 mg, 40%.

MS: ESP+(M+H)=514.

The title compound was characterised by an HPLC retention time of 23.30mins., using the HPLC conditions described in Example 35

EXAMPLE 31N-((5S)-3-(4-(1-Butyryloxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Triethylamine (101 mg) was added to a stirred solution of Example 6 (242mg) in dichloromethane (10 ml), followed by the dropwise addition ofbutyryl chloride (76 mg) in dichloromethane (0.2 ml). After stirring for30 minutes, additional triethylamine and butyryl chloride (as above)were added giving complete reaction after a further 30 minutes atambient temperature. The reaction mixture was washed with 2N HCl, water,saturated NaHCO₃ and saturated NaCl. The organic phase was dried overanhydrous Na₂SO₄ and evaporated to a crystalline solid. This waspurified by MPLC (using 4% MeOH/CH₂Cl₂ as eluant, Merck 9385 silica) andtriturated with ether to give the title compound. Yield=237 mg, 82%.

NMR (300 MHz, DMSO-D6)δ: 0.90 (t, 3H), 1.55 (m, 2H), 1.81 (s, 3H), 2.32(t, 2H), 2.55 (obscured), 3.40 (t, 2H), 3.56 (t, 1H), 3.64 (t, 1H), 3.75(q, 1H), 4.10 (m, 3H), 4.69 (m, 1H), 4.83 (d, 2H), 6.15 (broad, 1H),7.48 (m, 4H), 8.20 (t, 1H).

MS: ESP+(M+H)=443.

EXAMPLE 32N-((5S)-3-(4-(1-Decanoyloxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Using an analogous procedure to that described in Example 31, Example 6was acylated with decanoyl chloride (2×149 mg) to give the titlecompound. Yield=268 mg, 78%.

NMR (300 MHz, DMSO-D6)δ: 0.90 (t, 3H), 1.23 (s, 12(H), 1.55 (m, 2H),1.81 (s, 3H), 2.32 (t, 2H), 2.55 (obscured), 3.40 (t, 2H), 3.56 (t, 1H),3.64 (t, 1H), 3.75 (q, 1H), 4.10 (m, 3H), 4.69 (m, 1H), 4.83 (d, 2H),6.15 (broad, 1H), 7.48 (m, 4H), 8.20 (t, 1H).

MS: ESP+(M+H)=528.

EXAMPLE 33N-((5S)-3-(4-(1-Ethylaminocarboxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl-2-oxooxazolidin-5-ylmethyl)acetamide

Triethylamine (101 mg), followed by ethyl isocyanate (142 mg) were addedto a stirred solution of Example 6 (298 mg) in dichloromethane (10 ml).After stirring for 18 hours at ambient temperature, additionaltriethylamine and ethyl isocyanate (as above) were added giving completereaction after a further 24 hours. A precipitate of product was filteredoff and a second crop was obtained on reducing the volume. The combinedmaterial was recrystallised from ethanol to give the title compound.Yield=251 mg, 71%.

NMR (300 MHz, DMSO-D6)δ: 1.00 (t, 3H), 1.80 (s, 3H), 2.50 (obscured),3.00 (m, 2H), 3.40 (t, 2H), 3.55 (t, 1H), 3.65 (t, 1H), 3.73 (q, 1H),4.07 (m, 3H), 4.68 (m, 3H), 6.13 (broad, 1H), 7.27 (broad, 1H), 7.50 (m,4H), 8.21 (t, 1H).

MS: ESP+(M+H)=445.

EXAMPLE 34N-((5S)-3-(4-(1-Benzyloxyacetyloxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Using an analogous procedure to that described in Example 31, Example 6was acylated on a 2.0 mM scale with benzyloxyacetyl chloride (3×461 mg)to give the title compound. Yield=705 mg, 68%.

NMR (300 MHz, DMSO-D6)δ: 1.82 (s, 3H), 2.50 (obscured), 3.40 (t, 2H),3.58 (t, 1H), 3.66 (t, 1H), 3.73 (q, 1H), 4.10 (m, 3H), 4.24 (s, 2H),4.58 (s, 2H), 4.70 (m, 1H), 4.95 (d, 2H), 6.15 (broad, 1H), 7.35 (m,5H), 7.50 (m, 4H), 8.20 (t, 1H).

MS: ESP+(M+H)=522.

EXAMPLE 35N-((5S)-3-(4-(1-{4-t-Butylcyclohexylcarbonyl}-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Using an analogous procedure to that described in Example 20, the TFAsalt of Example 2 was reacted with 4-tert-butylcyclohexanecarboxylicacid in place of N-acetylglycine, to give the title compound. Yield=208mg, 58%.

MS: ESP+(M+H)=482.

The title compound was characterised by an HPLC retention time of 21.72mins., using the following HPLC conditions: Column: Hypersil ODS 5m;Flow rate: 1.5 ml/min.; UV: 254 nm; gradient parameters: Solvent A 1 mMTFA/water, Solvent B 1 mM TFA/acetonitrile; time 0.95% A/5B; time 3mins. 95% A/5% B; time 17 mins. 5% A/95% B; time 19 mins 95% A/5% B;time 20 mins 95% A/5% B.

EXAMPLE 36N-((5S)-3-(4-(1-{2-Hydroxy-decanoyl}-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Using an analogous procedure to that described in Example 20, the TFAsalt of Example 2 was reacted with 2-hydroxydecanoic acid in place ofN-acetylglycine, to give the title compound. Yield=252 mg, 65%.

MS: ESP+(M+H)=514.

The title compound was characterised by an HPLC retention time of 22.80mins., using the HPLC conditions described in Example 35.

EXAMPLE 37N-((5S)-3-(4-(1-{Pyrimid-2-yl}-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Using an analogous procedure to that described in Example 25, the TFAsalt of Example 2 was reacted on a 1.5 mM scale with 2-chloropyrimidine,to give the title compound. Yield=220 mg, 36%.

NMR (300 MHz, DMSO-D6)δ: 1.80 (s, 3H), 2.50 (obscured), 3.40 (t, 2H),3.73 (q, 1H), 3.98 (t, 2H), 4.10 (t, 1H), 4.30 (d, 2H), 4.69 (m, 1H),6.25 (s, 1H), 6.62 (t, 1H), 7.48 (m, 4H), 8.20 (t, 1H), 8.37 (d, 2H).

MS: ESP+(M+H)=394.

EXAMPLE 38N-((5S)-3-(4-(1-p-Toluenesulfonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Triethylamine (202 mg), followed by p-toluenesulfonyl chloride (171 mg)were added to a stirred suspension of the TFA salt of Example 2 (322 mg)in dichloromethane (10 ml). After stirring for 30 minutes at ambienttemperature, the reaction mixture had become a solution and the reactionwas complete. The solution was washed with 2N HCl, water, saturatedNaHCO₃ and saturated NaCl. The organic phase was dried over anhydrousNa₂SO₄ and evaporated to give a crystalline solid which was trituratedwith ether to give the title compound. Yield=306 mg, 87%.

NMR (300 MHz, DMSO-D6) δ: 1.79 (s, 3H), 2.35 (s, 3H), 2.50 (obscured),3.17 (m, 2H), 3.38 (m, 2H), 3.64 (broad, 2H), 3.70 (m, 1H), 4.08 (m,1H), 4.68 (m, 1H), 6.05 (broad, 1H), 7.40 (m, 6H), 7.68 (m, 2H), 8.20(t, 1H).

MS: ESP+(M+H)=470.

EXAMPLE 39N-((5S)-3-(4-(1-Hydroxyacetyl-1,2,3,4,5,6-hexahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

A mixture of Example 6 (242 mg) and ethanol (10 ml) was hydrogenatedover 10% palladium on charcoal (25 mg) at atmospheric pressure for 3hours. The catalyst was removed by Millipore filtration and the solventwas evaporated leaving an oil which crystallised on trituration withether to give the title compound. Yield=230 mg, 95%.

NMR (300 MHz, DMSO-D6)δ:1.50 (m, 2H), 1.75 (m, 2H), 1.80 (s, 3H), 2.70(m, 2H), 3.04 (t, 1H), 3.37 (t, 2H), 3.73 (m, 2H), 4.09 (m, 3H), 4.25(m, 2H), 4.69 (m, 1H), 7.23 (d, 2H), 7.42 (d, 2H), 8.20 (t, 1H).

MS: ESP+(M+H)=376.

EXAMPLE 40N-((5S)-3-(3-Fluoro-(2,3,4,5-tetrahydropyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Using an analogous procedure to that described in Example 39, Example 11was hydrogenated on a 0.6 mM scale to give the title compound inquantitative yield.

NMR (300 MHz, DMSO-D6)δ: 1.65 (m, 4H), 1.80 (s, 3H), 3.00 (m, 1H), 3.36(t, (2H), 3.44 (d of d, 2H), 3.70 (d of d, 1H), 3.90 (d of d, 2H), 4.07(t, 1H), 4.70 (m, 1H), 7.23 (d of d, 1H), 7.32 (t, 1H), 7.41 (d of d,1H), 8.20 (t, 1H).

MS: ESP+(M+H)=337.

EXAMPLE 41N-((5S)-3-(3,5-Difluoro-(2,3,4,5-tetrahydropyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Using an analogous procedure to that described in Example 39, Example 47was hydrogenated on a 4.23 mM scale to give the title compound (1.38 g,93%).

NMR (300 MHz, DMSO-D6)δ: 1.55 (d of d, 2H), 1.95 (m, 2H), 3.13 (m, 1H),3.38 (m, 4H), 3.69 (q, 1H), 3.91 (d of d, 2H), 4.08 (t, 1H), 4.72 (m,1H), 7.25 (d, 2H), 8.18 (t, 1H).

MS: ESP+(M+H)=355.

EXAMPLE 42N-((5S)-3-(3-Fluoro-4-(1-hydroxyacetyl-1,2,3,4,5,6-hexahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Using an analogous procedure to that described in Example 39, Example 9was hydrogenated on the scale of Example 39 to give the title compound(236 mg, 92%).

NMR (300 MHz, DMSO-D6) δ: 1.60 (m, 4H), 1.80 (s, 3H), 2.69 (t, 1H), 3.04(m, 2H), 3.39 (t, 2H), 3.37 (m, 2H), 4.08 (m, 3H), 4.48 (m, 2H), 4.70(m, 1H), 7.20 (d of d, 1H), 7.30 (t, 1H), 7.43 (d of d, 1H), 8.19 (t,1H).

MS: ESP+(M+H)=394.

EXAMPLE 43N-((5S)-3-(4-(1-Hydroxyacetyloxyacetyl-1,2,3,4,5,6-hexahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

A mixture of Example 34 (261 mg) and ethanol (10 ml) was hydrogenatedover 10% palladium on charcoal (125 mg) at atmospheric pressure for 3days. The catalyst was removed by Millipore filtration and the solventwas evaporated leaving an oil which crystallised on trituration withether to give the title compound. Yield=179 mg, 83%.

NMR (300 MHz, DMSO-D6)δ: 1.55 (m, 4H), 1.82 (s, 3H), 2.70 (m, 2H), 3.10(m, 1H), 3.39 (t, 2H), 3.70 (q, 1H), 3.80 (m, 1H), 4.09 (m, 3H), 4.41(m, 1H), 4.69 (m, 1H), 4.84 (s, 2H), 5.40 (t, 1H), 7.24 (d, 2H), 7.44(d, 2H), 8.20 (t, 1H).

MS: ESP+(M+H)=434.

EXAMPLE 44N-((5S)-3-(3,5-Difluoro-4-(1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

N-BOC-acetamide (3.1 g, Chem. Pharm. Bull., 36, 3125 (1988)) was addedto a solution of Reference Example 11 (5.3 g) in THF (100 ml), and themixture cooled in an ice-bath. Tributyl phosphine (4.8 ml, 3.89 g) and1,1′-(azodicarbonyl)-dipiperidine (4.9 g) were added and the mixtureallowed to stir at ice-bath temperature for 30 minutes after which aprecipitate was evident. The reaction was then stirred overnight atambient temperature. After filtration and evaporation in vacuo theresidue was purified on silica gel using a 1:1 mixture of isohexane andethyl acetate as eluant to give a solid (6.77 g). The solid wasdissolved in TFA (10 ml) and refluxed for a few minutes. The TFA wasremoved in vacuo and the residue dissolved in a mixture of ethyl acetateand methanol. The solvent was evaporated and trituration with ether gavethe title product (3.5 g, 58%) as the TFA salt (58%). The filtrate gavea further impure gum (1.25 g) which was suitable for furtherconversions.

NMR (300 MHz, DMSO-D6) d: 2.50 (broad, s, 2H), 3.40 (t, 2H), 3.71 (q,1H), 3.77 (broad, s, 2H), 4.11 (t, 1H), 4.74 (m, 1H), 5.89 (broad s,1H), 7.34 (d, 1H), 8.20 (t, 1H), 8.94 (broad s, 2H).

EXAMPLE 45N-((5S)-3-(3,5-Difluoro-4-(1-acetoxymethylcarbonyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Using an analogous reaction and work-up procedure to that described inExample 5, the TFA salt of Example 44 and acetoxy-acetylchloride werereacted on a 7.16 mM scale to give the title compound. Yield=2.62 g,81%.

NMR (300 MHz, DMSO-D6) δ: 1.81 (s, 3H), 2.08 (s, 3H), 2.30 (broad s,1H), 2.40 (broad s, 1H), 3.40 (t, 2H), 3.55 (t, 1H), 3.64 (t, 1H), 3.72(q, 1H), 4.08 (m, 3H), 4.74 (m, 1H), 4.83 (d, 2H), 5.85 (m, 1H), 7.30(d, 2H), 8.20 (t, 1H).

MS: ESP+(M+H)=452.

EXAMPLE 46N-((5S)-3-(3,5-Difluoro-4-(1-hydroxyacetyl-1,2,5,6-tetrahydro-4-pyridyl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Using an analogous procedure to that described in Example 6, Example 45(0.5 g) was converted to the title compound (solid 0.38 g, 84%).

NMR (300 MHz, DMSO-D6) d: 1.81 (s, 3H), 2.33 (broad d, 2H), 3.38 (t,2H), 3.51 (t, 1H), 3.66 (t, 1H), 3.70 (q, 1H), 4.08 (m, 3H), 4.12 (t,2H), 4.58 (broad d, 1H), 4.74 (m, 1H), 5.85 (d, 1H), 7.30 (d, 2H), 8.20(t, 1H).

MS: ESP+(M+H)=410.

EXAMPLE 47N-((5S)-3-(3,5-Difluoro-4-(2,3-dihydro-6H-pyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

N-BOC-acetamide (5.37 g, Chem. Pharm. Bull., 36, 3125 (1988)), followedby tributyl phosphine (8.3 ml) and 1.1′-(azodicarbonyl)-dipiperidine(8.52 g) were added to a stirred mixture of Reference Example 14 (7.0 g)and anhydrous THF (200 ml) in an ice-bath. The mixture was stirred for afurther 30 minutes at 0-5° C. and then stirred to ambient temperatureover-night. The mixture was filtered, the solid washed with THF and thecombined filtrates evaporated in vacuo and purified on solid gel (usinga 4:6 mixture of isohexane and ethyl acetate as eluant). There was thusobtained an oil, which was dissolved in TFA (20 ml) by slow addition ofTFA to the oil, refluxed briefly for few minutes and evaporated invacuo. The residue was taken up on ethyl acetate (200 ml) washed withsaturated NaHCO₃, the extracts counter-washed and the combined organicextracts evaporated in vacuo. The residue was purified on silica gel(using a mixture of 5% methanol and dichloromethane as eluant) to givethe title compound as a solid (5.4 g, 68%).

NMR (300 MHz, DMSO-D6) d: 1.82 (s, 3H), 2.26 (broad s, 2H), 3.18 (t,2H), 3.70 (q, 1H), 3.78 (t, 2H), 4.10 (t, 1H), 4.18 (q, 2H), 4.65 (m,1H), 5.89 (s, 1H), 7.26 (s, 1H), 7.33 (s, 1H), 8.19 (t, 1H).

MS: ESP+(m+H)=353.

EXAMPLE 48 N-((5S)-3-(4-(2-Methyl-3,6- and-5,6-dihydropyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Reference Example 15 (0.49 g), palladium(0) bis(dibenzylideneacetone)(0.86 g), triphenylarsine (0.115 g) and lithium chloride (0.24 g) weredissolved in degreased N-methyl morpholine (33 ml). The stannane(Reference Example 1) (0.75 g) was added and the solution stirred at 40°C. for 18 hours. The mixture was then treated with aqueous potassiumfluoride (5 ml, 2M), stirred for 0.5 hours and filtered through Celite.The solution was drowned with water (250 ml) and extracted with ethylacetate (2×30 ml). The combined organics were washed with water (2×100ml), dried and evaporated to the crude product (0.333 g, 54%) which waspurified by firstly silica-gel MPLC [using a mixture of 2% MeOH andCH₂Cl₂ as eluant] and then preparative TLC [using a mixture of 13% MeOHand CH₂Cl₂ as eluant] to give the title mixture of 2-methyl regioisomers(0.054 g, 9%).

NMR (300 MHz, CDCl₃)d: 1.30-1.39 (m, 3H), 2.00-2.05 (s/s, 3H), 2.27-2.39(broad m, 1.5H), 2.57-2.69 (m, 0.5H), 3.57-3.97 (4H, m), 4.00-4.20 (m,2H), 4.30-4.40 (m, 1H), 4.72-4.81 (m, 1H), 6.00 (s, 0.5H), 6.05-6.10 (m,0.5H), 6.40 (broad s, 1H), 7.39 (dd, 2H) and 7.45 (d, 2H).

MS: ESP+(M+H)=331.

EXAMPLE 49N-((5S)-3-(4-(2,6-Dimethyl-2,3-dihydro-6H-pyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Reference Example 18 (0.656 g), palladium(0) bis(dibenzylideneacetone)(0.123 g), triphenylarsine (0.164 g) and lithium chloride (0.338 g) weredissolved in degassed N,N-dimethylformamide (18 ml). The stannane(Reference Example 1) (1.07 g) was added after 5 minutes and stirringwas continued for 19 hours at 40° C. Aqueous potassium fluoride (6.3 ml,2M) was added and stirring continued for 15 minutes whereupon themixture was filtered through Celite and evaporated to an oil. The oilwas purified by silica-gel MPLC [using a mixture of ethyl acetate andisohexane increasing in polarity from 75% to 100% ethyl acetate aseluant] to afford a foam which was triturated with diethyl ether to givethe title compound as a powder (0.679 g, 78%).

NMR (300 MHz, CDCl₃) d: 1.33 and 1.35 (d/d, each 3H), 2.01 (s, 3H),2.28-2.35 (m, 2H), 3.55-3.82 (m, 4H), 4.05 (t, 1H), 4.36-4.25 (m, 1H),4.72-4.82 (m, 1H), 6.00 (d, 1H), 6.01-6.10 (m, 1H), 7.40 (d, 2H) and7.50 (d, 2H).

MS: ESP+(M+H)=345.

EXAMPLE 50

There is no compound with Example No. 50.

EXAMPLE 51 N-((5S)-3-(4-(2-Benzyloxymethyl-3,6- and-5,6-dihydropyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Reference Example 21 (0.28 g), palladium(0) bis(dibenzylideneacetone(0.039 g), triphenylarsine (0.052 g) and lithium chloride (0.107 g) weredissolved in degassed N,N-dimethylformamide (8 ml). The stannane(Reference Example 1) (0.338 g) was added after 5 minutes and stirringwas continued for 21 hours at 40° C. Aqueous potassium fluoride (2.0 ml,2M) was added and stirring continued for 20 minutes whereupon themixture was evaporated. The residue was partitioned between ethylacetate (40 ml) and water (10 ml), and the organic layer dried andevaporated to an oil which was purified by silica-gel MPLC [using amixture of 3% MeOH and CH₂Cl₂ as eluant]. The resultant foam wastriturated with diethyl ether to give a mixture of the title compounds(0.204 g, 58%).

NMR (300 MHz, CDCl₃) d: 2.01 (s, H), 2.29-2.73 (m, 2H), 3.54-3.94 (m,6H), 4.06 (t, 1H), 4.14-4.23 (m, 0.5H), 4.39-4.53 (m, 1.5H), 4.56-4.70(m, 2H), 4.71-4.83 (m, 1H), 6.07 (d, 1H), 6.15 (t, 1H) and 7.29-7.51 (m,9H).

MS: ESP+(M+H)⁺=437.

EXAMPLE 51AN-((5S)-3-(4-(2-Benzyloxymethyl-3,6-dihydropyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Example 51A was prepared in an identical fashion to Example 51, butstarting from Reference Example 24 instead of Reference Example 21.

NMR (300 MHz, CDCl₃) d: 2.01 (s, 3H), 2.28-2.50 (m, 2H), 3.54-3.94 (m,6H), 4.09 (t, 1H), 4.32-4.50 (m, 2H), 4.61 (d, 1H), 4.67 (d, 1H),4.72-4.83 (m, 1H), 6.10 (br s, 1H), 6.18 (t, 1H), 7.28-7.50 (m, 9H).

MS: ESP+ (M+H)=437.

EXAMPLE 52 N-((5S)-3-(4-[2-Hydroxymethyl-3,6- and-5,6-dihydropyran4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

The benzyl ether Example 51 (0.158 g) in dry dichlormethane (7 ml) at 0°C. was treated with boron trichloride-dimethyl sulfide (0.097 g, 0.27ml) and stirred for 3 days. TLC indicated consumption of startingmaterial. Methanol (5 ml) was added and stirring continued for 20minutes. The solution was evaporated and the residue purified bysilica-gel MPLC [using a mixture of 2% MeOH and CH₂Cl₂ as eluant] togive a mixture of the title compounds (0.043 g, 35%).

NMR (300 MHz, CDCl₃) d: 2.01 (s, 3H), 2.21-2.70 (m, 2 H), 3.55-3.85 (m,6H), 4.09 (t, 1H), 4.10-4.20 (m, 0.5H), 4.35-4.45 (m, 1.5H), 4.70-4.82(m, 1H), 5.98-6.15 (m, 2H) and 7.35-7.50 (m, 4H).

MS: (ESP⁺) (M+H)=347.

EXAMPLE 52AN-((5S)-3-(4-(2-Hydroxymethyl-3,6-dihydropyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Example 52A was prepared in an identical fashion to Example 52, butstarting from Example 51A rather than Example 51.

NMR (300 MHz, DMSO-D6) d: 1.82 (s, 3H), 2.11-2.40 (m, 2H), 3.37-3.79 (m,7H), 3.99-4.35 (m, 2H), 4.10 (t, 1H), 4.62-4.80 (m, 1H), 6.18-6.25 (m,1H), 7.40-7.55 (m, 4H), 8.20 (t, 1H).

MS: ESP+ (M+H)=347.

EXAMPLE 53 N-((5S)-3-(4-(2-Acetamidomethyl-3,6- and-5,6-dihydropyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

Trimethyl phosphite (1 ml) was added slowly under argon to a stirredsolution of the azide Reference example 23 (0.138 g) in dimethoxyethane(2 ml) at 50° C. After 2.25 hours, the solution was evaporated,redissolved in dimethoxyethane (2 ml) and treated with 6N hydrochloricacid (0.065 ml). The mixture was refluxed for 0.25 hours, cooled andstirred at ambient temperature for 0.5 hours. The solution wasevaporated to the crude amine hydrochloride. The amine hydrochloride(0.22 mmol) in dimethoxyethane (2 ml) and water (0.5 ml) was taken to pH9 with 2.5M sodium hydroxide solution and then treated with aceticanhydride (0.075 g). After 2.5 hours, the solution was evaporated andpurified by Isolute silica-gel chromatography [using a mixture of 5%MeOH and CH₂Cl₂ as eluant] to give the title mixture of compounds (0.063g, 45%).

NMR (300 MHz CDCl₃) d: 1.99, 2.02 and 2.03 (s/s/s, together 6H),2.30-2.40 (m, 1H), 3.20-3.32 (m, 1H), 3.58-3.83 (m, 6H), 4.09 (t, 1H),4.10-4.19 and 4.30-4.41 (m/m, together 2H), 4.74-4.82 (m, 1H), 5.98 and6.09 (each broad s, together 2H), 6.43 (broad s, 1H), 7.32-7.40 and7.43-7.50 (m/m, together 4H).

MS: ESP+ (M+H)=388.

EXAMPLE 54N-((5S)-3-(4-(2-{Pyrimid-2-ylthio}methyl-3,6-dihydropyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide

The alcohol Example 52A (0.162 g), 2-mercaptopyrimidine (0.105 g) andN,N-dimethylformamide dineopentyl acetal (0.326 g, 0.393 ml) in dryacetonitrile (10 ml) were refluxed for 4.5 hours. The solution wascooled, evaporated and purified by silica-gel MPLC [using a mixture of6% MeOH and CH₂Cl₂ as eluant] to give an oil which was triturated withdiethyl ether to afford the title compound in crystalline form (0.134 g,63%).

NMR (300 MHz, CDCl₃) d: 2.02 (s, 3H), 2.30-2.72 (m, 2H), 3.39-4.00 (m,6H), 4.05 (t, 1H), 4.13-4.62 (m, 2H), 4.72-4.82 (m, 1H), 6.09-6.25 (m,2H), 6.98 (t, 1H), 7.40 (d, 2H), 7.49 (d, 2H), 8.52 (d, 2H).

MS: ESP+ (M+H)=441.

EXAMPLES 55 TO 98 Carboxamides

Using a similar procedure to that described in Example 35, but startingwith the appropriate carboxylic acid instead of4-tert-butylhexanecarboxylic acid the following compounds of the formulaXIV (Table A) were prepared by robotic synthesis (using a robot machinemanufactured by Zymark). The procedure used is described below.

The TFA salt of Example 2 in DMF (0.75 mM, 4 ml) was added to theappropriate carboxylic acid (0.863 mM) under argon. To this was thenadded a solution of N-methylmorpholine in DMF (1 mM, 1 ml) and asolution of N-hydroxybenzotriazole in DMF (0.863 mM, 1 ml). The mixturewas then stirred at ambient temperature for 5 minutes after which time asolution of 1-ethyl-3-dimethylaminopropyl-carbodiimide (EDC) in DMF(0.863 mmole, 3 ml) was added. The reaction was then stirred at ambienttemperature overnight. The solvent was evaporated using centrifugalevaporation (SAVANT AES2000) using radiant cover for 3 hours. Theresidue was dissolved in CH₂Cl₂ (5 ml). The organics were sequentiallywashed with 1N HCl (4 ml), water (4 ml), saturated NaHCO₃ (4 ml) andbrine (5 ml). The solvent was again removed by centrifugal evaporation(SAVANT AES2000) using low heat for 3 hours and the products transferredinto 16×49 mm vials.

The less pure products were subjected to further purification byBondelut Chromatography using conditions comparable to those of the TLCsystem used in earlier Examples ie. 5-10% MeOH/CH₂Cl₂. The relevantfractions were combined and the solvent removed by centrifugalevaporation (SAVANT AES2000) on low heat for 3 hours. The products werethen transferred into 16×49 mm vials.

The compounds were analysed by mass spectroscopy and were characterisedby HPLC retention time, using the HPLC conditions described in Example35.

TABLE A N-Acyl compounds: (XIV)

Example MS Mol Ion Hplc retention No. R (Formula (XIV)) (M + H) time(min.) 55 [1R-(1A,2B,3A)]-(+)-3-methyl-2 513 19.17(nitromethyl)-5-oxocyclopentaneacetyl- 56 2-butoxyacetyl- 430 19.57 575-fluoroindole-3-acetyl- 491 19.78 583-acetyl-2,2-dimethylcyclobutyl-acetyl- 482 19.17 592-cyclopenten-1-acetyl- 424 20.15 60 2-napthoxyacetyl- 500 21.63 61oxamoyl- 463 19.95 62 N-t-butoxycarbonylglycyl- 473 19.08 63methylthioacety-l 404 17.77 64 There is no compound with Example No. 6465 N-methyl-2-pyrroloyl- 423 19.12 66 trifluoroacetyl 412 20.12 673-(2-furyl)-acryloyl- 436 19.60 68 3-furoyl- 410 18.10 693-(2-thienyl)-acryoyl- 452 20.23 70 thiophene-2-acetyl- 440 19.28 71thiophen-3-oyl- 426 18.78 72 There is no compound with Example No. 72 73indole-3-acetyl- 473 19.50 74 There is no compound with Example No. 7475 There is no compound with Example No. 75 76 (2-pyrimidylthio)-acetyl468 17.68 77 3,4-diydro-2H-pyranoyl- 426 18.77 78 5-(O-methyl)-comenoyl468 15.15 79 1,4-benzodioxan-6-acetyl- 492 19.32 803-(phenylsulfonyl)-propionoyl- 512 18.88 81 4-(aminosulfonyl)-benzoyl-499 16.93 82 4-(diethylaminosulfonyl)-benzoyl- 583 22.38 834-(dimethylamino)-butyroyl- 429 15.20 84 N-acetyl-L-prolyl- 455 16.23 852,3,4-trimethoxycinnamoyl- 536 20.42 86 There is no compound withExample No. 86 87 (R)-5-oxo-2-tetrahydrofuroyl- 428 16.43 887-oxo-octanoyl- 456 18.38 89 There is no compound with Example No. 89 902-benzofuranoyl- 460 20.95 91 indole-1-acetyl- 473 20.97 92sulfolanyl-3-acetyl- 476 16.67 93 4-oxo-4H-1-benzo-2-pyranoyl- 488 19.1894 There is no compound with Example No. 94 95 indole-3-oyl- 459 18.9896 2-(n-propylthio)-nicotinoyl- 495 20.62 97 2-methoxy-pyridin-3-oyl-451 17.95 98 2,3-dihydro-5-oxothiazolo-[3,2-A]- 496 16.37pyrimidin-6-oyl-

EXAMPLES 99 TO 139 Sulfonamides

Using a similar procedure to that described in Example 38, but startingwith the appropriate sulfonyl chloride instead of p-toluenesulfonylchloride the following compounds of the formula XV (Table B) wereprepared by robotic synthesis (using a robot machine manufactured byZymark). The procedure used is described below.

The TFA salt of Example 2 (279 mg, 0.65 mM) was suspended in CH₂Cl₂ (10ml). To this was added triethylamine (243 μl) and then a solution of theappropriate sulfonyl chloride in CH₂Cl₂ (0.78 mM in 5 ml). The mixturewent into solution after 10-15 minutes and the reaction was then stirredat ambient temperature for a further 4 hours. The compounds weresubjected to purification by Bondelut Chromatography using conditionscomparable to those of the TLC system used in earlier Examples ie. 5-10%MeOH/CH₂Cl₂. The relevant fractions were combined and the solventremoved by centrifugal evaporation (SAVANT AES2000) on low heat for 3hours. The products were then transferred into 16×49 mm vials.

The compounds were analysed by mass spectroscopy and were characterisedby HPLC retention time, using the HPLC conditions described in Example35.

TABLE B N-Sulfonyl compounds: (XV)

Example MS Mol Ion Hplc retention No. R (Formula (XV)) (M + H) time(min.)  99 8-quinoline-sulfonyl- 507 19.93 100 2-naphthalene-sulfonyl-504 22.82 101 2-methoxycarbonylphenyl-sulfonyl 514 20.65 1024-fluorobenzene-sulfonyl- 474 21.38 103 3-chloropropane-sulfonyl- 45620.17 114 4-chlorobenzene-sulfonyl- 490 22.43 1154-carboxybenzene-sulfonyl-  498* 19.75 116 isopropylsulfonyl- 422 19.28117 b-styrylsulfonyl- 482 21.88 118 ethanesulfonyl- 408 18.35 1191-butanesulfonyl- 436 20.70 120 1-octanesulfonyl- 492 25.07 1212-chlorobenzene-sulfonyl- 490 21.67 122 3-carboxybenzene-sulfonyl-  498*19.23 123 3-trifluoromethylbenzene-sulfonyl- 524 22.77 1242,2,2-trifluorethanesulfonyl- 462 20.48 125 5-chlorothiophene-sulfonyl-496 22.72 126 2-(pyrid-2-yl)-thiophene-5-sulfonyl- 539 21.68 1272,4-difluorobenzene-sulfonyl- 492 21.62 128 3-fluorobenzene-sulfonyl-474 21.50 129 4-acetamidobenzene-sulfonyl- 513 18.90 1301-methylimidazol-4-yl-sulfonyl- 460 17.03 1315-(isoxazol-3-yl)-thiophene-2-sulfonyl- 529 21.50 1325-bromothiophene-2-sulfonyl- 540 22.83 134 4-cyanobenzene-sulfonyl- 48120.85 135 4-trifluoromethoxybenzene-sulfonyl- 540 22.15 1364-trifluoromethylbenzene-sulfonyl- 524 22.93 1373,4-dimethoxybenzene-sulfonyl- 516 20.27 1385-dimethylamino-1-naphthalene-sulfonyl- 549 20.15 139 benzenesulfonyl-456 21.00 *M − H NB. There are no compounds with Example Nos. 104-113and 133.

EXAMPLE 140

The following illustrate representative pharmaceutical dosage formscontaining the compound of formula I, or a pharmaceutically-acceptablesalt thereof (hereafter compound X), for therapeutic or prophylactic usein humans:

(a) Tablet I mg/tablet Compound X 100 Lactose Ph.Eur 179 Croscarmellosesodium 12 Polyvinylpyrrolidone 6 Magnesium stearate 3 (b) Tablet IImg/tablet Compound X 50 Lactose Ph.Eur 229 Croscarmellose sodium 12Polyvinylpyrrolidone 6 Magnesium stearate 3 (c) Tablet III mg/tabletCompound X 1 Lactose Ph.Eur 92 Croscarmellose sodium 4Polyvinylpyrrolidone 2 Magnesium stearate 1 (d) Capsule mg/capsuleCompound X 10 Lactose Ph.Eur 389 Croscarmellose sodium 100 Magnesiumstearate 1 (e) Injection I (50 mg/ml) Compound X 5.0% w/v Isotonicaqueous solution to 100%

Buffers, pharmaceutically-acceptable cosolvents such as polyethyleneglycol, polypropylene glycol, glycerol or ethanol or complexing agentssuch as hydroxy-propyl β cyclodextrin may be used to aid formulation.

Note

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art. The tablets (a)-(c) may be entericcoated by conventional means, for example to provide a coating ofcellulose acetate phthalate.

What is claimed is:
 1. A compound of formula (I):

wherein R¹ is OH; R² and R³ are each independently hydrogen or fluoro;R⁴ and R⁵ are each independently hydrogen, C₁₋₄alkyl, carboxy,C₁₋₄alkoxycarbonyl or independently R⁷; R⁶ is hydrogen, C₁₋₄alkyl,hydroxy, C₁₋₄alkoxy, or C₂₋₄alkanoylalkoxy; D is NR⁷; R⁷ is hydrogen,cyano, 2-(C₁₋₄alkoxycarbonyl)ethenyl, 2-cyanoethenyl,2-cyano-2-(C₁₋₄alkyl)ethenyl, 2-(C₁₋₄alkylaminocarbonyl)ethenyl, AR or atretrazole ring system, optionally mono-substituted in the 1- or2-position of the tetrazole ring, wherein the tetrazole ring system isjoined to the nitrogen in NR⁷ by a ring carbon atom; or R⁷ is R¹⁰C(═O)—,R¹⁰SO₂— or R¹⁰C(═S)—; or R⁷ is R^(d)OC(R^(e))═CHC(═O)—,R^(f)C(═O)C(═O)—, R^(g)N═C(R^(h))C(═O)— or R^(i)NHC(R^(j))═CHC(═O)—; orR⁷ is R¹⁴CH(R¹³)(CH₂)_(m)—; R¹⁰ is AR, cyclopentyl or cyclohexyl,wherein the last two mentioned cycloalkyl rings are optionally mono- ordi-substituted by substituents selected from C₁₋₄alkyl, hydroxy,C₁₋₄alkoxy, C₁₋₄alkylthio, acetamido, C₁₋₄alkanoyl, cyano andtrifluoromethyl; or R¹⁰ is C₁₋₄alkoxycarbonyl, hydrogen, amino,C₁₋₄alkylamino, diC₁₋₄alkalkylamino,2,3-dihydro-5-oxothiazolo-[3,2-A]pyrimidin-6-yl, 2-(2-furyl)ethenyl,2-(2-thienyl)ethenyl, 2-phenylethenyl, wherein the phenyl substituent isoptionally substituted by up to three substituents independentlyselected from C₁₋₄alkoxy, halo or cyano; or R¹⁰ is3,4-dihydropyran-2-yl, coumal-5-yl, 5-methoxy-4-oxopyran-2-yl,N-acetylpyrrolidin-2-yl, 5-oxotetrahydrofuran-2-yl, benzopyranone orC₁₋₁₀alkyl, wherein C₁₋₁₀alkyl is optionally substituted by hydroxy,cyano, halo, C₁₋₁₀alkoxy, trifluoromethyl, C₁₋₄alkoxy-C₁₋₄alkoxy,C₁₋₄alkoxy-C₁₋₄alkoxy-C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkoxycarbonyl,amino, C₁₋₄alkylamino, diC₁₋₄alkylamino, C₁₋₆alkanoylamino,C₁₋₄alkoxycarbonylamino, N—C₁₋₄alkoyl-N—C₂₋₆alkanoylamino,C₁₋₄alkylS(═O)_(p)NH—, C₁₋₄alkS(═O)_(p)(C₁₋₄alkyl)N—,fluoroC₁₋₄alkylS(═O)_(p)NH—, fluoroC₁₋₄alkS(═O)_(p)(C₁₋₄alkyl)N—,phosphono, C₁₋₄alkoxy(hydroxy)phosphoryl, diC₁₋₄alkoxyphosphoryl,C₁₋₄alkylS(═O)_(q)—, CY or phenylS(═O)_(q)—, wherein the phenyl group isoptionally substituted by up to three substituents independentlyselected from C₁₋₄alkoxy, halo and cyano; or R¹⁰ is R¹¹C(═O)OC₁₋₆alkylor R¹²O—; R¹¹ is an optionally substituted 5- or 6-membered heteroaryl,optionally substituted phenyl, C₁₋₄alkylamino, benyloxyC₁₋₄alkalkyl, oroptionally substituted C₁₋₁₀alkyl; R¹² is optionally substitutedC₁₋₆alkyl; R¹³ is fluoro, cyano, C₁₋₄alkoxy, C₁₋₄alkylsulfonyl,C₁₋₄alkoxycarbonyl or hydroxy, provided that when m is 0, R¹³ is notfluoro or hydroxy; R¹⁴ is hydrogen or C₁₋₄alkyl; >A—B is of the formula>C═C(R^(a))—, >CHCHR^(a)— or >C(OH)CHR^(a); > represents two singlebonds R^(a) is hydrogen or C₁₋₄alkyl; R^(d) is C₁₋₆alkyl; R^(e) ishydrogen or C₁₋₆alkyl; or Rd and Re together form a C₃₋₄alkylene chain;R^(f) is hydrogen, C₁₋₆alkyl, hydroxylC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl,amino, C₁₋₄alkylamino, diC₁₋₄alkylamino, C₁₋₆alkoxy,C₁₋₆alkoxyC₁₋₆alkoxy, hydroxyC₂₋₆alkoxy, C₁₋₄alkylaminoC₂₋₆alkoxy ordiC₁₋₄alkylaminoC₂₋₆alkoxy; R^(g) is C₁₋₆alkyl, hydroxy, or C₁₋₆alkoxy;R^(h) is hydrogen or C₁₋₆alkyl; R^(i) is hydrogen, C₁₋₆alkyl, optionallysubstituted phenyl or an optionally substituted 5- or 6-memberedheteroaryl; R^(j) is hydrogen or C₁₋₆alkyl; AR is optionally substitutedphenyl, optionally substituted phenylC₁₋₄alkyl, optionally substituted5- or 6-membered heteroaryl, optionally substituted naphthyl or anoptionally substituted 5/6 or 6/6 bicyclic heteroaryl ring system, inwhich the bicyclic heteroaryl ring systems may be linked via an atom ineither of the rings comprising the bicyclic system, and wherein themono- and bicyclic heteroaryl ring systems are linked via a ring carbonatom; CY is 4-, 5- or 6-membered cycloalkyl ring, a 5- or 6-memberedcycloalkenyl ring, naphthoxy, thiophen-2-yl, indol-1-yl, indol-3-yl,pyrimidin-2-ylthio, 1,4-benxoioxan-6-yl, sulfolan-3-yl or pyridin-2-yl,wherein any of the aforementioned ring systems in CY may be optionallysubstituted by up to three substituents independently selected fromhalo, C₁₋₄alkyl, acyl, oxo and nitroC₁₋₄alkyl, m is 0 or 1; p is 1 or 2;and q is 0, 1, or 2; or a pharmaceutically acceptable salt thereof. 2.The compound according to claim 1, wherein R⁷ is an optionallysubstituted phenylC₁₋₄alkyl.
 3. The compound according to claim 2wherein R² is optionally substituted benzyl or phenethyl.
 4. Thecompound according to claim 1 wherein: R⁴ and R⁵ are each independentlyhydrogen, cyano, 2-(C₁₋₄alkoxycarbonyl)ethenyl, 2-cyanoethenyl,2-cyano-2-(C₁₋₄alkyl)ethenyl, 2-(C₁₋₄alkylaminocarbonyl)ethenyl, AR or atretrazole ring system, optionally mono-substituted in the 1- or2-position of the tetrazole ring; or R⁴ and R⁵ are each independentlyhydroxy, bromo, C₁₋₄alkyl, C₁₋₄alkanoylamino-C₁₋₄alkyl,hydroxyC₁₋₄alkyl, carboxy, C₁₋₄alkoxycarbonyl, AR-oxymethyl, R¹⁰C(═O)—,R¹⁰SO₂— or R¹⁰C(═S)—; or R⁴ and R⁵ are each independentlyR^(d)OC(R^(c))═CHC(═O)—, R^(f)C(═O)C(═O)—, R^(g)N═C(R^(h))C(═O)— orR^(i)NHC(R^(j))═CHC(═O)—; or R⁴ and R⁵ are each independentlyR¹⁴CH(R¹³)(CH₂)_(m)—.
 5. A compound of formula (I):

wherein R¹ is OH; R² and R³ are each independently hydrogen or fluoro;R⁴ and R⁵ are each independently hydrogen, C₁₋₄alkyl, carboxy,C₁₋₄alkoxycarbonyl or independently R⁷; R⁶ is hydrogen, C₁₋₄alkyl,hydroxy, C₁₋₄alkoxy, or C₂₋₄alkanoylalkoxy; D is a protected amine; R⁷is hydrogen, cyano, 2-(C₁₋₄alkoxycarbonyl)ethenyl, 2-cyanoethenyl,2-cyano-2-(C₁₋₄alkyl)ethenyl, 2-(C₁₋₄alkylaminocarbonyl)ethenyl, AR or atretrazole ring system, optionally mono-substituted in the 1- or2-position of the tetrazole ring, wherein the tetrazole ring system isjoined to the nitrogen in NR⁷ by a ring carbon atom; or R⁷ is of theformula R¹⁰C(═O)—, R¹⁰SO₂— or R¹⁰C(═S)—; or R⁷ is of the formulaR^(d)OC(R^(e))═CHC(═O)—, R^(f)C(═O)C(═O)—, R^(g)N═C(R^(h))C(═O)— orR^(i)NHC(R^(j))═CHC(═O)—; or R⁷ is of the formula R¹⁴CH(R¹³)(CH₂)_(m)—;R¹⁰ is AR, cyclopentyl or cyclohexyl, wherein the last two mentionedcycloalkyl rings are optionally mono- or di-substituted by substituentsselected from C₁₋₄alkyl, hydroxy, C₁₋₄alkoxy, C₁₋₄alkylthio, acetamido,C₁₋₄alkanoyl, cyano and trifluoromethyl; or R¹⁰ is C₁₋₄alkoxycarbonyl,hydrogen, amino, C₁₋₄alkylamino, diC₁₋₄alkalkylamino,2,3-dihydro-5-oxothiazolo-[3,2-A]pyrimidin-6-yl, 2-(2-furyl)ethenyl,2-(2-thienyl)ethenyl, 2-phenylethenyl, wherein the phenyl substituent isoptionally substituted by up to three substituents independentlyselected from C₁₋₄alkoxy, halo and cyano; or R¹⁰ is3,4-dihydropyran-2-yl, coumal-5-yl, 5-methoxy-4-oxopyran-2-yl,N-acetylpyrrolidin-2-yl, 5-oxotetrahydrofuran-2-yl, benzopyranone orC₁₋₁₀alkyl, wherein C₁₋₁₀alkyl is optionally substituted by hydroxy,cyano, halo, C₁₋₁₀alkoxy, trifluoromethyl, C₁₋₄alkoxy-C₁₋₄alkoxy,C₁₋₄alkoxy-C₁₋₄alkoxy-C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkoxycarbonyl,amino, C₁₋₄alkylamino, diC₁₋₄alkylamino, C₁₋₆alkanoylamino,C₁₋₄alkoxycarbonylamino, N—C₁₋₄alkoyl-N—C₂₋₆alkanoylamino,C₁₋₄alkylS(═O)_(p)NH—, C₁₋₄alkS(═O)_(p)(C₁₋₄alkyl)N—,fluoroC₁₋₄alkylS(═O)_(p)NH—, fluoroC₁₋₄alkS(═O)_(p)(C₁₋₄alkyl)N—,phosphono, C₁₋₄alkoxy(hydroxy)phosphoryl, diC₁₋₄alkoxyphosphoryl,C₁₋₄alkylS(═O)_(q)—, CY or phenylS(═O)_(q)—, wherein the phenyl group isoptionally substituted by up to three substituents independentlyselected from C₁₋₄alkoxy, halo and cyano; or R¹⁰ is R¹¹C(═O)OC₁₋₆alkylor R¹²O—; R¹¹ is an optionally substituted 5- or 6-membered heteroaryl,optionally substituted phenyl, C₁₋₄alkylamino, benyloxyC₁₋₄alkalkyl, oroptionally substituted C₁₋₁₀alkyl; R¹² is optionally substitutedC₁₋₆alkyl; R¹³ is fluoro, cyano, C₁₋₄alkoxy, C₁₋₄alkylsulfonyl,C₁₋₄alkoxycarbonyl or hydroxy, provided that when m is 0, R¹³ is notfluoro or hydroxy; R¹⁴ is hydrogen or C₁₋₄alkyl; >A—B is of the formula>C═C(R^(a))—, >CHCHR^(a)— or >C(OH)CHR^(a); > represents two singlebonds R^(a) is hydrogen or C₁₋₄alkyl; R^(d) is C₁₋₆alkyl; R^(e) ishydrogen or C₁₋₆alkyl; or Rd and Re together form a C₃₋₄alkylene chain;R^(f) is hydrogen, C₁₋₆alkyl, hydroxylC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl,amino, C₁₋₄alkylamino, diC₁₋₄alkylamino, C₁₋₆alkoxy,C₁₋₆alkoxyC₁₋₆alkoxy, hydroxyC₂₋₆alkoxy, C₁₋₄alkylaminoC₂₋₆alkoxy ordiC₁₋₄alkylaminoC₂₋₆alkoxy; R^(g) is C₁₋₆alkyl, hydroxy, or C₁₋₆alkoxy;R^(h) is hydrogen or C₁₋₆alkyl; R^(i) is hydrogen, C₁₋₆alkyl, optionallysubstituted phenyl or an optionally substituted 5- or 6-memberedheteroaryl; R^(j) is hydrogen or C₁₋₆alkyl; AR is optionally substitutedphenyl, optionally substituted phenylC₁₋₄alkyl, optionally substituted5- or 6-membered heteroaryl, optionally substituted naphthyl or anoptionally substituted 5/6 or 6/6 bicyclic heteroaryl ring system, inwhich the bicyclic heteroaryl ring systems may be linked via an atom ineither of the rings comprising the bicyclic system, and wherein themono- and bicyclic heteroaryl ring systems are linked via a ring carbonatom; CY is 4-, 5- or 6-membered cycloalkyl ring, a 5- or 6-memberedcycloalkenyl ring, naphthoxy, thiophen-2-yl, indol-1-yl, indol-3-yl,pyrimidin-2-ylthio, 1,4-benxoioxan-6-yl, sulfolan-3-yl or pyridin-2-yl,wherein any of the aforementioned ring systems in CY may be optionallysubstituted by up to three substituents independently selected fromhalo, C₁₋₄alkyl, acyl, oxo and nitroC₁₋₄alkyl, m is 0 or 1; p is 1 or 2;and q is 0, 1, or 2; or a pharmaceutically acceptable salt thereof. 6.The compound according to claim 5, wherein R⁴ and R⁵ are eachindependently hydrogen, cyano, 2-(C₁₋₄alkoxycarbonyl)ethenyl,2-cyanoethenyl, 2-cyano-2-(C₁₋₄alkyl)ethenyl,2-(C₁₋₄alkylaminocarbonyl)ethenyl, AR or a tretrazole ring system,optionally mono-substituted in the 1- or 2-position of the tetrazolering; or R⁴ and R⁵ are each independently hydroxy, bromo, C₁₋₄alkyl,C₁₋₄alkanoylamino-C₁₋₄alkyl, hydroxyC₁₋₄alkyl, carboxy,C₁₋₄alkoxycarbonyl, AR-oxymethyl, R¹⁰C(═O)—, R¹⁰SO₂— or R¹⁰C(═S)—; or R⁴and R⁵ are each independently R^(d)OC(R^(e))═CHC(═O)—, R^(f)C(═O)C(═O)—,R^(g)N═C(R^(h))C(═O)— or R^(i)NHC(R^(j))═CHC(═O)—; or R⁴ and R⁵ are eachindependently R¹⁴CH(R¹³)(CH₂)_(m)—.
 7. The compound according to claim5, wherein the amine of D is protected with formyl, aralkyl,di-p-anisylmethyl, furylmethyl, lower alkoxycarbonyl, loweralkenyloxycarbonyl, aryl lower alkoxycarbonyl, trialkylsilyl,alkylidene, benzylidene or substituted benzylidene.
 8. The compoundaccording to claim 7, wherein the aralkyl is benzyl or substitutedbenzyl.
 9. The compound according to claim 8, wherein the substitutedbenzyl is p-methoxybenzyl, nitrobenzyl, 2,4-dimethoxybenzyl ortriphenylmethyl.
 10. The compound according to claim 7, wherein thelower alkoxycarbonyl is t-butoxycarbonyl.
 11. The compound according toclaim 7, wherein the lower alkenyloxycarbonyl is allyloxycarbonyl. 12.The compound according to claim 7, wherein the aryl lower alkoxycarbonylis benzyloxycarbonyl, p-methoxybenzyloxycarbonyl,o-nitrobenzyloxycarbonyl or p-nitrobenzyloxycarbonyl.
 13. The compoundaccording to claim 7, wherein the trialkylsilyl is trimethylsilyl ort-butyldimethylsilyl.
 14. The compound according to claim 7, wherein thealkylidene is methylidene.
 15. The compound(5R)-hydroxymethyl-3-(3-fluoro-4-(N-benzyl-1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-one.